Digestion & Absorption

salivary pancreatic endoglycosidases neutral chloride short

Lumenal digestion of starch: Two enzymes are involved - ________ amylase and _________ amylase. Both amylases are identical in action. Both are _________, hydrolyzing internal a1,4 linkages of amylose and amylopectin. Both enzymes have optimal activity at _________ pH and are activated by ___________ ions. The action by salivary amylase is of very _______ duration because it is inactivated in the stomach by the acid pH.

alcoholics heart

Deficiency: Deficiency common in _________ and in people from Far-East where polished rice is the staple diet. Over cooking of food and raw fish consumption can also cause deficiency. Deficiency disorder is called beriberi. Three types of beriberi are recognized: - Dry beriberi- mainly in older adults, associated with neurological symptoms such as degeneration of sensory and motor nerves. - Wet beriberi- associated with vascular symptoms such as edema and heart failure. - Infantile beriberi- occurs in breast-fed infants of mothers who are thiamin deficient. Very lethal, death occurs from _______ failure. Thiamin deficiency due to chronic alcoholism and hyperemesis in some genetically predisposed people (mutations in transketolase with reduced affinity for TPP) known as Wernicke-Korsakoff syndrome characterized by apathy, loss of memory and abnormal eye movements in genetically prone individuals. Source: Pork, yeast, whole grains and legumes are richest sources of thiamin. Outer layers of seeds are particularly rich. RDA is 1.0-1.5 mg/day.

pancreatic proteases neutral zymogens

Intestinal phase is initiated by ____ _____ present in the exocrine pancreatic secretion. These enzymes are responsible for lumenal phase and are active at ______ pH. These are secreted as inactive precursors called _____.

DUODENUM ferric (Fe3+) divalent Ferrous- Fe2+ DMT1- divalent methyl ion transporter- Proton Ferrous Ferritin Ferroprotin transferrin ferric body ferrous C- ascorbic acid reductant Hepcidin liver Hemochromatosis absorption diabetes Beta Bronze beta higher

Iron Absorption: -remember the figure: Where does it occur?? --> _____- the only place that absorbs iron, in the duodenal Enterocyte and you take iron, and most of the dietary iron exists in the oxidized form called _____, but our intestine cannot absorb iron in the trivalent form (Fe3+) only the _____form can be absorbed. Therefore there is an enzyme on the brush border membrane (you don't have to remember) called Ferric Reductase- just remember the intestine only absorbs_____****** NOT Ferric. and this Ferrous is absorbed via a transporter known as ________ very easy because ferrous is a divalent metal and therefore the divalent methyl ion transporter 1 transports this ferrous in association with a _______! - the second proton coupled nutrient transporter discovered in the mammalian cell (first was PEPT1 and second is DMT1) and it takes _______ inside. and once the Ferrous is inside, it can be stored in the form of _____, or it can be transferred out of the cell into the blood by a protein known as _________- a transporter in the basolateral membrane which transports the ferrous iron out of the intestinal cell and into the blood. But inside we are talking about Ferrous and as soon as the ferrous goes out into the blood it gets converted back to the oxidized ferric form and then loaded on a protein known as __________- the circulatory form of iron. Therefore the transferrin binds ____ - and then takes the iron from the intestine to the rest of the _______. Therefore this is the mechanism of iron absorption. What is the bottleneck in iron absorption: the conversion of Iron from the ferric into the ____ form (at BBM)- because unless you do this you cannot absorb iron, and because of that- anyone who is given iron supplementation is also given Vitamin _____, a water soluble vitamin- an it's a very important _______ (can reduce things ) ascorbate reduces the ferric into the ferrous form, therefore normally you have the ferric reductase enzyme, but you can facilitate it further by giving Vitamin C- therefore all pregnant women who are recommended to take iron supplementation are also told to take Vitamin C to increase the absorption of iron in the small intestine. There is a hormone we discovered known as ________- the only known hormone now which regulates iron homeostasis. The hepcidin is produced in the ______ and then controls iron absorption in the intestinal tract. -this process of iron absoprtion is impaired in ______________- a genetic disorder, the patients with this always have excesss iron in their body--> iron overload disease, responsible for increase in iron because it increases ___________ of iron. Therefore amount of iron absorbed in gut is facilitated in pateitns with Hemochromatosis and they accumulate iron chronically to very high levels- it is a genetic disorder, they are born with it- so they continuously have too much iron absorbed and their body- every tissue gets loaded with iron. Because of that iron accumulation under the skin, if you are white and have this you don't have to tan ever because presence of iron under the skin makes you look tan, and they also have ______ because the _____ cells of the pancreas get destroyed because of excess iron and therefore they cannot secrete insulin and get diabetes- how do you differentiate between type 1 and type 2 diabetes? --> it is called ________ Diabetes - because white people with excess iron gives the skin a natural tan and therefore the bronze color. This pigmentation is due to excess iron under skin and diabetes due to destruction of _____ cell. The excess iron and therefore hemoglobin level will be much ________ than normal and they do not suffer from anemia- because there is excess hemoglobin. and these are the diseases associated with iron disorder.

portal vein lacteals

It is important to note that the digestion products of dietary carbohydrates and proteins enter _____ ____ and are presented directly to liver. Liver absorbs these nutrients (sugars and amino acids) and uses them for metabolism or storage. In contrast, the digestion products of dietary fat enter ________ and are carried via thoracic duct into the subclavian vein. These nutrients (triglycerides) thus enter systemic circulation and are presented to adipose tissue and skeletal muscle where they are used for metabolism or storage.

NAD+ and NADP+ (nicotinamide adenine dinucleatide phosphate) Pellagra tryptophan

Niacin: -needed for two different coenzme forms: -_____ and _______ important thing: deficiency causes ___________!! known as disease of three D's !!- Dimentia, Dermatitis, Diarrhea -intestinal complication, skin complication, and neurological complication. -remember the link between tryptophan and Niacin, because Niacin can be synthesized in your body using__________ as the precursor!!!**********

peptidases

The brush border phase of protein digestion is carried out by the ________ associated with the brush border membrane. The enzymes are aminopeptidase A, aminopeptidase N, dipeptidylpeptidase IV and dipeptidylcarboxypeptidase (angiotensin converting enzyme, ACE). Peptidases (proteases) can be divided into two groups and the substrate specificity of these enzymes are given below: 1. Endopeptidases (or endoproteases) 2. Exopeptidases

peptide monomers intracellular peptides

The final products of protein digestion by pancreatic and brush border peptidases are a mixture of amino acids (20%) and small peptides (80%). Amino acids are absorbed by amino acid transport systems whereas small peptides (containing 2 or 3 amino acids) are absorbed by the ________ transport system. This is in contrast to carbohydrate digestion where dietary carbohydrates are completely broken down to ________ before absorption occurs. The intracellular phase of protein digestion is carried out by ________ peptidases which hydrolyze the absorbed peptides. The final products of protein digestion which appear in blood is predominantly free amino acids, though small peptides resistant to hydrolysis do end up in blood to some extent. Thus, the protein digestion products are absorbed into the intestinal cells primarily as ______, but what exits from the cells into blood is primarily free amino acids.

Iron, Calcium, and Folic Acid Carbohydrates, proteins and Fats Vitamins B12 Bile Acids water ileum liver ileum enterohepatic Na, Cl, and K HCO3- Na Cl- K+ HCO3- Bicarbonate Acidosis potassium

A few things you need to know: -intestinal tract is not uniform-- do not do the same functions --duodenum- primarily responsible for absorption of ______, ______, and ____ ______- 3 important nutrients absorbed maximally in duodenum --jejunum: primarily absorbed are the digestion products of _________, __________ and ________ and all ____________- whether water or fat soluble, except for B12 -- Ileum: ______ (exception for vitamins), and ______ ________ -> B12 is a ________ soluble vitamin and it is absorbed in the Ileum - if you have a condition where ileum is diseased or taken out surgically, then you will have a B12 deficiency, doesn't matter if jejunum and duodenum are functional--> because______ is what determines your B12 nutrition in your body -> Bile Acids which are secreted by the _______ into the bile duct, come through to the intestine, does it's job and then goes go to the ______ and gets reabsorbed back into the liver in a process called ______________ circulation of bile acids (will go into detail tomorrow) so bile acids only absorbed in ileum. -so you have to know segmental differentiation of the absorption process- where each of the nutrients get absorbed. In the Ileum what happens to the electrolyte absorption? -what happens with Na, Cl, HCO2, and K in Small Intestine: place where you: -absorb ____, _____, and ______ BUT you secrete the _________!!!** in Colon/ Large intestine: -____ absorbed -_____ absorbed -_____ SECRETED -________ SECRETED Why is it important?- say patient has secretory diarrhea- too much fluid in the lumen causing secretory diarrhea. If it happens to arise from pathology of the small intestine - what will be the consequence? what is secreted? ___________- and therefore if the the secretory diarrhea originates from the small intestine then the patient is going to lose bicarbonate a lot--> patient will get Metabolic ___________! - because patient is losing a lot of HCO3- , but there will be no change in the plasma level of potassium, because the potassium is not secreted in the small intestine - but if you have another patient in which the secretory diarrhea originates in the colon due to the pathology in the colonic epithelial cells, then that person is going to lose lots of _______ and a lot of bicarbonate, so not only will they suffer from metabolic acidosis, but also HYPOKALEMIA- because circulating levels of potassium will decrease, so if you describe your patient as having hypokalemic metabolic acidosis you know the defect lies in the Colon and not the small intestine.

apoprotein B chylomicron

Abetalipoproteinemia - absence of __________ ____ leading to defect in _________ formation and defect in triglyceride transport from the intestine

blood supply carbohydrate protein lacteals

Absorption : -Hydrophilic nutrients, ions, and water primarily enter ______ ____. This applies to products of _________ and _____ digestion, and also water-soluble vitamins. -Fat (lipid) digestion products primarily enter lymphatic ________. This applies also to fat-soluble vitamins (ADEK) . Thoracic duct then empties the contents into subclavian.

chylomicrons retinol-binding protein retinal 11-cis-retinal rhodopsin trans 11-cis-retinal

Absorption and transport: Retinol esters contained in _______ are taken up by, and stored in, the liver (called Ito cells or Stellate cells). Carried to extrahepatic tissues bound to plasma _________. Uptake of retinol into the cells is mediated by specific receptors expressed on cell surface. Functions: Retinal- Most thoroughly studied area of vitamin A physiology is its role in visual process. In retina, retinol is oxidized to _______ and isomerized to __________. 11-Cis-retinal forms a complex with opsin, a protein found in rod cells, to form _______, the visual pigment. When rhodopsin is exposed to light, 11-cis-retinal undergoes photochemical isomerization to all-_______retinal, which results in the separation of all-trans retinal and opsin. The ____________ is then regenerated by the isomerization of all-trans retinal in the retina.

ileum Na+ micelles hepatocytes

Absorption of Bile Salts The principal site of bile salt absorption is the _______. The transport process is active and is ______- dependent. Na+ is cotransported with bile salts. Absorption in the ileum occurs from the _________. The absorbed bile salts leave the intestinal cell via the basal-lateral membrane and enters the portal circulation. From there they are taken up by ___________ and secreted again into bile. This process is called enterohepatic circulation.

heme heme Fe2+ phosphates, phytates and oxalates C H+

Absorption of Iron Dietary iron contains both inorganic iron and _______ in which inorganic iron predominates. However, _____ iron is absorbed more effectively than inorganic iron. Many intraluminal factors affect the absorption of inorganic iron but not that of heme. Iron is released from heme inside the mucosal cells by heme oxygenase and transferred into the blood as inorganic iron. Iron is absorbed faster as _____ than as Fe3+- because ferric iron is insoluble above pH 3 whereas ferrous iron remains soluble at pH 8. The conversion of Fe3+ to Fe2+ is facilitated by ferric reductase, an enzyme associated with the intestinal (duodenal) brush border membrane. Dietary constituents such as carbonates, ________,_______,_______ reduce iron absorption because they form insoluble complexes with iron. In contrast, dietary constituents such as orange juice and vitamin _____supplements promote iron absorption because vitamin C reduces Fe3+ to the more absorbable Fe2+ form. Transport of Fe2+ across the brush border membrane is mediated by a divalent cation transporter and is energized by an electrochemical ____ gradient. The same transporter also recognizes Zn2+, Mn2+, and Cu2+ as substrates.

hypokalemia

Absorption of K+ Absorption of K+ in the small intestine is thought to be primarily by passive mechanisms, significantly influenced by the direction of water flow and by transepithelial potential difference. The brush border membrane of ileum also possesses a K+-H+-ATPase which may be involved in active absorption of K+ against a concentration gradient, energized by ATP hydrolysis. In this process, transport of K+ into the cell is coupled to secretion of H+ into the lumen. While small intestine absorbs Na+, Cl-, and K+, and secretes HCO3-, colon absorbs only Na+ and Cl- but secretes K+ and HCO3-. Therefore, hypersecretion of fluid in colon leads to metabolic acidosis (due to loss of HCO3-) as well as _____________ (due to loss of K+).

acetazolamide amiloride

Absorption of Na+ and Cl- 1. Thesodiumpump:TheNa+-K+-ATPaseisresponsibleforactiveNa+transportfrom the intestinal cell to blood. It is present exclusively in the basal-lateral membranes. It is inhibited by ouabain, a cardiac glycoside. 2. Passive diffusion of Na+: Some Na+ may enter small intestinal cells by passive diffusion down its electrochemical gradient. 3. Na+-H+ exchanger: This exchanger is predominantly present in the brush border membrane of small intestinal as well as colonic epithelial cells. The system operates to transport Na+ from the lumen into the cell and H+ from the cell into the lumen. It is responsible for the presence of acidic microclimate pH on the surface of the brush border membrane. 4.NaCltransport:TheelectroneutralNaCltransportacrossthebrushbordermembrane of small intestine occurs due to the action of two exchangers (antiporters) - Na+-H+ exchanger and C1--HC03- exchanger. This process is inhibited by _____________, an inhibitor of carbonic anhydrase because it would reduce the generation of HC03- within the cell. 5. Organic solute-coupled Na+ transport: Cotransport of Na+ with glucose, amino acids, bile salts, and water-soluble vitamins in the small intestine contributes to Na+ absorption to some extent. 6. Aldosterone-stimulated Na+ transport: This process occurs in the apical (luminal) membranes of the distal colon. This is due to a Na+ channel and occurs passively down the electrochemical Na+ gradient. These channels are highly sensitive to inhibition by low concentrations of ___________. Aldosterone stimulates the Na+ channel.

megaloblastic anemia green

Also called vitamin B9. Folic acid (pteroylmonoglutamic acid) is composed of a pterin ring attached to p-aminobenzoic acid (PABA) and conjugated with glutamic acid. In tissues, folic acid is polyglutamylated (5-6 glutamic acid residues) at the -carboxy- group. Humans cannot synthesize PABA or attach the first glutamic acid. Sulfa drugs are structural analogs of PABA and inhibit the synthesis of folic acid in bacteria. Deficiency: Folic acid deficiency is the most common vitamin deficiency in the US, particularly among pregnant women and alcoholics. Women taking contraceptives are also at risk for folate deficiency. Primary result of deficiency is ______ _______(decreased DNA synthesis in erythropoetic cells), growth failure and leukopenia. Fatigue, acne, sore tongue and neuropathies are other symptoms. Folate deficiency during pregnancy can result in Neural Tube Defects (NTD). Source: Liver, egg yolk, orange juice and ______ vegetables such as broccoli, spinach, and bell peppers. RDA is ~200 μg in adults and ~400 μg during pregnancy and lactation.

Acetyl-CoA Pyruvate Propionyl-CoA hair flora

BIOTIN Also called vitamin H. Consists of an imidazole ring fused with a tetrahydrothiophene ring with a pentanoic acid side chain. Function: It is important for the carboxylation of intermediary metabolites. Biotin is tightly bound to lysine residue in carboxylase enzymes. Holocarboxylase synthetase attaches biotin to all carboxylases. Biotin bound to lysine is called biocytidine. Biotin, as a cofactor for four ATP- dependent carboxylases, serves as a carrier for activated carbon dioxide: 1. __________carboxylase: acetyl-CoA Malonyl-CoA (fatty acid biosynthesis) 2. _________ carboxylase: Pyruvate oxaloacetate (gluconeogenesis) 3. __________ carboxylase: Propionyl-CoA methylmalonyl-CoA (catabolism of odd- and branched- chain fatty acids and the AAs valine & isoleucine) Vitamin K and biotin are both involved in carboxylation reactions. Vitamin K plays a role in carboxylating glutamic acids in proteins while biotin plays a role in carboxylating intermediary metabolites. Vitamin K participates in a single carboxylation reaction (- carboxylation) whereas all other carboxylation reactions in the body require biotin. Deficiency: Not common, but can occur in individuals eating large quantities of raw eggs. Hypotonia, developmental delay, ______ loss and skin rash are symptoms of biotin deficiency. Genetic defect in holocarboxylase synthetase and biotinidase (the enzyme which releases biotin from the AA lysine) causes multiple carboxylase deficiency. Source: Intestinal ______ is the major source of biotin. Also found in liver, peanuts and chocolate.

carboxylasess pyruvate carboxylase Acetyl CoA carboxylase Propionyl-CoA carboxylase pyruvate lactate alanine acetyl coA propionic

Biotin: -all ___ (except vit k carboxylase) require this -important carboxylases: _____ ______- found in gluconeogenesis (needed to convert pyruvate into oxaloacetate which can feed into the gluconeogenesis process) - _____ _____ _____- needed for FA biosynthesis -________ _____ _______- metabolism of BCAA valine and lucine these are the 3 important carboxylases you need to remember which are biotin dependent- nothing to do with vitamin K - so if you have a Biotin deficiency what will happen? --> _______ level will o up --> _______ level will go up --> ______ level will go up --> _____ _____ level will go up --> ________ acid level will go up because those 3 enzymes cannot function without biotin and tehrefore the precursor substrate will get elevated in the body.

methylmalonate

Both folate and cobalamin deficiency will result in Hyperhomocystinemia, but cobalamin-B12 deficiency will also cause accumulation of __________. *****

'' liver Homocysteine methyltransferase Methylmalonyl-CoA mutase HCl and pepsin ileum anemia megaloblastic anemia pernicious anemia ileum (Crohn's disease)

COBALAMIN Also called Vitamin B12. Largest, most complex, unique (contains the metal ion cobalt), and unlike other water-soluble vitamins, is stored in the ______. Function: B12 is cofactor for two enzymes: 1. _______ __________ (methionine synthase): methylcobalamin is the cofactor. Homocysteine + N5-methyltetrahydrofolate Methionine + tetrahydrofolate 2. ____________ ________: 5'-deoxyadenosylcobalamin is the cofactor. Methylmalonyl Co-A Succinyl Co-A Absorption: In stomach, ______ and _______ release vitamin B12 from protein bound sources. Free vitamin attaches to cobalophilin (also called haptocorrin), a vitamin B12 binding protein secreted by the salivary glands. In the duodenum, cobalophilin is hydrolyzed by pancreatic proteases and the released vitamin B12 forms complex with intrinsic factor, a small glycoprotein secreted by the gastric parietal cells. Vitamin B12-intrinsic factor complex is internalized in the _______ via interaction with a specific receptor (IFCR - IF/cobalamin receptor). Deficiency: Dietary deficiency of B12, rare and seen in strict vegetarians, causes ________. Folate is "trapped" in N5-methyltetrahydrofolate form. N5-N10-Methylene and N10-formyl forms of tetrahydrofolate, needed for the synthesis of nucleotides, are not produced. Therefore, symptoms are similar to folate deficiency- ________ ______. Prolonged deficiency leads to neurological problems, which is irreversible when demyelination sets in. Destruction of gastric parietal cells due to autoimmune disease or generation of anti-intrinsic factor antibodies will result in the failure of B12 absorption. B12 deficiency due to lack of intrinsic factor is called ______ ____. Inflammation of the _____ _______ or surgical removal of the ileum will also lead to B12 deficiency. Source: Synthesized exclusively by microorganisms. Present in animal products such as meat, poultry, milk and fish. Not present in plant products and yeast. B12-Deficiency is common in strict vegetarians. RDA is 2.0 μg/day.

small intestine protein trypsinogen trypsin protein brush border pancreas

Clinical Note: Enteropeptidase (enterokinase) deficiency: - what does the enteropeptidase do, so if it's genetically defective what are consequences? -the defect lies in the ______ _______ because these are the cells which make the enteropeptidase, and when there is a defect (EP not made or it is inactive) it will interfere with the ______ digestion. Because without enteropeptidase you cannot activate__________ into _______. And without trypsin, you cannot activate chymotrypsinogen, proelastase, and other things, therefore enteropeptidase deficiency will lead to very severe, defective _________ digestion and absorption, therefore, that is actually important. Just wants us to know that enteropeptidase is actually an intestinal enzyme associated with the _______ ______ membrane of the small intestine**********. It does not come with the trypsinogen and chymotrypsinogen from the _________. b/c if it comes from there even within the pancreas it will start hydrolyzing trypsinogen and activating it to trypsin and it can cause the problem.

protein HCl pepsin Haptocholine Intrinsic Factor salivary HCl and IF Haptocholine pancreatic proteases IF ILEUM B12 IF stomach and pancreas gastrectomy pancreatitis ileal methionine synthase methyl malonyl CoA Mutase HyperHomocystinemia

Cobalamin- B12 -very complicated absorptive process -now taken in to the diet usually bound to _______ , and therefore this first has to be release--> it goes ot the stomach and in the stomach you have the B12 bound to the protein--> and then it's released into the free form here, the release of the free form requires _______ to denature the protein and also _______ which can hydrolyze the protein and release the B12. (you have to remove the protein to release the B12 with HCl and pepsin) -the stomach all contains two different B12 binding proteins. One is called __________ and other is called ______ _____- both can bind B12. Haptocholine comes from the _______ gland intrinsic factor comes from parietal cells of the stomach- so teh IF is produced from the same cels that produce the HCl. so the parietal cells secrete ____ and ____ and both can bind B12, but in the acidic pH- B12 binds ___________ but not IF. therefore in the stomach what you have is B12 bound to Haptocholine and the Intrinsic Factor in the free form, and then they all go to the Jejunum. In the Jejunum this haptocholine is broken down by the _______ _______- because it brings trypsin, chymotrypsin and elastase. and therefore these pancreatic proteases break down haptocholine- release B12 and now the B12 binds to the ______, the proteases don't break down the IF because IF is a protein not sensitive to pancreatic hydrolysis. It stays almost stable and therefore the IF binds to the B12, and if you go to the Jejunum what do you find? no HC because it is all digested by pP now you ahve B12 bound to IF, still no absorption all those things happen in the stomach and jejunum- and then they go to the Ileum. in the iluem is the place where it is abosrbed!!!!________ is the selective place where the B12 is absobed!!! In the ileum now contains B12 and IF, and there is a receptor in the BBm- known as _____ _____ receptor, and the receptor binds to that and takes the B12 inside: so B12 gets absorbed in the Intrinsic factor bound B12 form. remember... ILEUM IS SITE FOR B12 ABSOROPTION, but the ______ and ______ a re both also necessary for B12 absorption. And therefore if you have a ___________- you'll have B12 deficiency -if you have ___________- you'll have B12 deficiency - if you have _______ resection or inflammation of the ileum- you'll have B12 deficiency -because you need stomach, parietal cells, pancreas, ielum, for normal B12 absorption- how much you absorb every day 1um, and for that all those things- have no idea why it's so complicated (you can get 1mg injection and be good for one year) because B12 is needed for only two enzymes in your body? - ______ ______ which converts homocysteine into methionine and the second one is ____ _____ ____ ____- which converts mthyl malonyl CoA into succinyl CoA- therefore if you have B12 deficiency you'll have _____________ and Methylmalonyl acid will go up too. and that s how you differentiate it from Folic acid def. which we saw in bipchem B12 deficiency: what is involved is important too: homocysteine and how to differentiate

chloride

Cystic fibrosis patients (homozygous) and cystic fibrosis carriers (heterozygous) may be resistant to cholera and Travelers' diarrhea due to defective _________ channel in the intestinal brush border membrane.

rickets osteomalacia hypercalcemia calcinosis UV

Deficiency: Extremely common; can be due to- low intake, limited exposure to sunlight (children, older and people in higher altitudes), race (skin color), kidney, intestinal, and parathyroid diseases In children-________-soft pliable bones due to incomplete mineralization of the collagen matrix of bone. This lead to beaded ribs, muscular hypotonia, knock-knees or bowlegs and deformities of the thorax. In adults-___________- demineralization (increased ratio of unmineralized:mineralized bone) of preexisting bones results in increased susceptibility to fracture. Toxicity: Vitamin D is the most toxic of all vitamins. Results in nausea, thirst, loss of appetite, and stupor. Enhanced calcium absorption and bone resorptions results in __________ resulting in the deposition of calcium in soft tissues of many organs, particularly arteries and kidneys - term called __________. Source: Salt water fish, fortified dairy products and _______ exposure of skin. RDA for adults is 5 μg.

oligosaccharides cellulose, hemicellulose, pectins colon propionic diverticulosis cholesterol

Diet also contains a small amount of unavailable carbohydrates which include indigestible___________ (e.g. raffinose) and dietary fiber (______, ______, _______, etc.). These carbohydrates are not digested in the small intestine. They are fermented by bacterial enzymes in the _______ and the fermentation products such as acetic acid, ___________ acid and butyric acid are absorbed to a small extent into the blood. These short chain fatty acids are excellent nutrients for colonic epithelium and are essential for normal colonic function. Dietary fiber increases stool volume and promotes regularity of bowel movement, is beneficial in irritable bowel syndrome and ____________ and reduces serum _________ and colon cancer incidence.

glucose. amylopectin

Diet may contain very small amounts of glycogen, which is also a polymer of __________ It is found in animal tissues, mainly in liver and muscle and structurally it is similar to ____________ but with more branch points.

Cellulose short cancer duodenum or the jejunum colon

Dietary Fiber: - we all take the dietary fiber- very important for colonic health -the fiber is primarily made up of cellulose, or hemicellulose, pectins, lignens, gums, and these are the things that we get from vegetables and they all contain the fiber. We cannot digest any of these in the small intestine and absorb the carbohydrates present there. For example: there is no difference between cellulose and starch, both are glucose polymers - when you take starch you can absorb the glucose in the blood, but when you take cellulose even though it is exactly like starch except the bonding is different between the glucose residues, now your enzymes cannot digest the cellulose- now why do you have to take the cellulose? because the colon is full of bacteria, and you have to provide them their food because you have evolved lots of bacteria over millions of years and our colon has billions and billions of bacteria, and it's a symbiotic relationship- and therefore not only do you provide a home for the bacteria to reside there you also have to feed them --> ___________ is the food for the bacteria. Now since it's a glucose polymer, the bacteria of the enzymes which can digest the cellulose use the glucose as their energy source, and when they do that- they ferment the glucose and make a special class of metabolites called ________ chain fatty acids: Acetate, proponate and Butyrate , and in your colon the concentration of these short chain fatty acids can be as high as 100mmolar. And these 100 mmol of the short chain fatty acids are believed to be the protectors against the colon ________, but nobody has looked at how do these short chain fatty acids get into the colonic epithelium to protect against the carcinogenesis, and therefore, now we cloned the transporter from the kidney, we didn't know what it was doing same transporter expressed in the colon, and if it was present there you don't get the cancer. Now, when he read the paper, it was very easy that the transporter actually accepts Acetate, Propionate, and Butyrate as the substrates taken into the colonic epithelium and then protect against the colon because it's simply logical --> realized what he cloned was actually a short chain fatty acid transporter, and the short chain fatty acid transporter is not expressed in the _______ or _______ because there are no bacteria there and they don't make acetate, butyrate and propionate in the early part of the intestine - only in the _________, so when you look longitudinally at the expression of the transporter duodenum: nil, jejunum: no, ileum: a little bit, colon is the highest amount- where functionally it is relevant. - important because microbiome, and they have discovered that the pathology of the microbiome can also be a factor in diseases like autism. Can you imagine linking the gut to the brain, these bacteria seem to make you what you are- why we have to eat dietary fiber.

starch and glycogen sucrose and lactoses

Digestion of carbohydrates can be divided into two phases - lumenal digestion and membrane digestion. Both phases are responsible for the digestion of ________ and __________ whereas only membrane digestion is involved in the hydrolysis of _________ and ___________.

Gastric Intestinal

Digestion of proteins: _____ phase _______ phase o lumenal phase o brush border phase o intracellular phase

micelles acidic

Fat Absorption The fat digestion products (monoglycerides, fatty acids, cholesterol, phospholipids) are present in the intestinal lumen in the form of _______, aided by the presence of bile salts. These products are absorbed into the intestinal cell from these micelles. On the surface of the brush border membrane, pH is _______ (microclimate acid pH) due to secretion of H+ from the cell. This acidic pH causes micellar dissociation. Uptake of these products through the brush border membrane is a passive process and is mostly due to their lipid solubility.

lipase absorption

Fat soluble vitamins: Requires bile salts and pancreatic ________ & esterases; defects in bile (e.g., cholestasis) and pancreatic secretion (pancreatic insufficiency due to cystic fibrosis or defective digestion and absorption as in untreated celiac disease) will result in decreased ___________. Individuals suffering from fat malabsorption usually have deficiency of multiple fat- soluble vitamins.

Megaloblastic Anemia

Folate: you can read this but main thing to remember is the connection between Folic Acid deficiency, _____ _____ and the Neural Tube Defect. Think about this picture- babies born with deficient folic acid- and it causes the without brain formation, the spinal problem and therefore all pregnant women are told to take folic acid supplements because that is the only one vitamin supplementation that has been shown to reduce incidence of neural tube defects.

gastric secretions, salivary secretions, pancreatic secretions and liver neutralized bile pancreatic S Secretin stomach parietal bicarbonate Cholangial intrahepatic cholangiocytes pancreas. parietal cholangiocytes I duodenum protein and fat proton pancreas amylases, proteases, lipases, blood stream pancreas Gallbladder contracts bile fat and the protein Bile Acids

For Digestion and Absorption: -You need various secretions: ______, _______, _______, and _______secretions- all play a role in digestion and absorption of all nutrients in your body. Now from there, if you look at the stomach, the pH is around 1-2 because of acid secretion. -when the stomach contents actually go to the duodenum, here the pancreatic duct and bile duct come in, and when they dump all the bile secretion and pancreatic secretion into the duodenum and therefore, once you go to duodenum, the pH has to be ___________ b/c the pH is acidic only in the stomach, but if you look at duodenum after the entry of the pancreatic and bile ducts--> the pH becomes almost neutral. -Now How does it happen? --> Pancreatic and BIle Duct bring in lots of bicarbonate- bicarb present in the _____ and ___________ secretions neutralizes the protons in the stomach secretion making the pH return to normal -Now What's the signal for bicarbonate secretion? --> when the proton goes down into duodenum, and the excess proton acts on the specific endocrine cells of the duodenum called ____ cells--> secrete __________ = a gastrointestinal hormone secreted by S cells present in the duodenum in response to protons coming from the stomach, now once secretin is made- has 3 diff functions: 1. gets into circulation and goes back into the __________ and then reduces HCl secretion from the stomach and what are the cell types that secrete HCl in the stomach?-- ________ cells- so they respond to Secretin and reduce the production of HCl so that the amount of acid going into the duodenum is reduced so that the pH can be neutralized 2. It increases the _________ secretion from the liver- and primarily not in the liver the hepatocyte actually the cells which line the bile duct called the ___________ cells- the ones which line the bile duct (hepatocytes are the ones that secrete bile) therefore most of the time the bile which brings the bicarbonate comes not from the liver- but from the __________ bile duct present in the liver, and the cells which secrete the bicarbonate are the ___________- functional cells which line the bile duct and secrete bicarbonate, and they are stimulated to secrete HCO3- by Secretin. 3. It stimulates the bicarbonate from the_________. So pancreatic secretion now contains lots of bicarbonate and therefore secretin has 3 functions: reduces acid production from the _________cells , increases bicarb secretion from _________ and pancreas and thereby the proton which acts as a signal can be neutralized by the bicarbonate. It makes sense, because if the secretin is secreted in response to protons , then it has to increase the bicarbonate solution to neutralize the pH. The second one: -When the stomach contents enter the duodenum, they also bring fat and protein digestion products, because there is a little bit of digestion that occurs in the stomach and the digestion products enter the duodenum and when the fat and protein products come into the duodenum, they act on specific types of endocrine cells called _____ cells- which secrete cholecystokinin. so the chlecystokinin is secreted form the __________ in response to the _______ and ______ digestion products coming from the stomach. Now since the stimulant for the CCK secretion is the fat and protein digestion products, it will makes sense the cholecystokinin role has nothing to do with the ________. It gets into the systemic circulation, goes to the _________, and then promotes an enzyme rich pancreatic secretion, because pancreatic secretion brings _____, _______, and _______ all those enzymes needed for digeston of fat and protein. Therefore, if CCK secretion is released in the duodenum, from the I cells in response to fat and protein digestion products, and that hormone acts on the pancreas to produce more lipase and more proteases, so they can come into the intestine and act on the fat and the protein. The CCK gets secreted into the _______ ______ and then goes to the pancreas to act on that. So that is one of the functions of CCK, to promote enzyme rich secretion from the _________. The second function is the name of the hormone: -Cholecyst- is another term for __________. because it's the cyst that stores chole- bile. Therefore the gallbladder is synonymous with cholecyst and kinin- means activate (protein kinase when something activates the protein), therefore the Cholecystokinin is a hormone that activates the gallbladder. What does it does it do? It goes into the systemic circulation, acts on the gallbladder and _________ the gallbladder- by contracting the gallbladder- the ______ can be released into the duct and then come into the small intestine. Now CCK increases the bile secretion into the intestine by contracting the gallbladder, increases the enzymes present in the pancreas- and both are needed to digest the ______ and ______. ______ _____ are needed for fat digestion, and the enzymes are needed for both fat and protein digestion. Therefore it makes sense that which hormones are secreted in response to the constituents coming from the stomach. Therefore these are the basics that you need to know.

Pyruvate dehydrogenase α-ketoglutarate dehydrogenase Branched-chain keto-acid dehydrogenase Transketolase

Function: Has a central role in energy-yielding metabolism, especially that of carbohydrates. TPP acts as a cofactor in the oxidative decarboxylation of α-keto acids (associated with reduction of NAD+ and production of a molecule of CO2) and transketolase reactions. TPP is the prosthetic group: 1. a-Ketoacid dehydrogenase complexes: a. ____ ______ complex- converts pyruvate to acetyl CoA b. _______ _______ complex- converts α-ketoglutarate to succinyl CoA c. ______ ______ ______ complex- catabolism of branched- chain amino acids 2. ________- an enzyme in the pentose phosphate pathway a. Ribose 5-phosphate and xylulose 5-phosphate to glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate. b. Erythrose 4-phosphate and xylulose 5-phosphate to fructose 6-phosphate and glyceraldehyde 3-phosphate.

2 endopeptidase aromatic 5.0

Gastric phase of protein digestion occurs in the stomach and is carried out by pepsin. This enzyme is secreted by chief cells of the stomach in an inactive form, called pepsinogen. The acidic pH activates the enzyme. It has an optimum pH around ____. It is an __________ with specificity for peptide bonds involving _______ and bulky branched chain amino acids. The enzyme is inactivated above pH _____. Therefore, pepsin is active only in stomach and gets inactivated once the stomach contents enter the intestine where the pH is neutral (~ 7.5).

SGLT1 glucose-galactose lactose absorbed lumen osmotic pressure water osmotic diarrhea colon ferment hydrogen flatus portal blood Colon starch glucose FRUCTOSE GLUT 5 glucose and galactose same glucose, galactose and sucrose higher hydrogen glucose-galactose

Glucose-galactose malabsorption: -genetic disorder, defect lies in ________ -have intestinal cell, SGLT1 in brush border membrane, which transports the glucose or galactose along with the sodium, if this transporter is defecting you get ______-__ malabsorption, but you don't get fructose malabsorption because it does not use SGLT1 -babies are born with the defect, as soon as they are born they drink breast milk- consists of ______ gets digested to glucose and galactose, and glucose and galactose are produced in the GI tract because lactase is normal but they are not ________ due to genetic defect in transporter--> glucose and galactose accumulate in the ______--> this increases _____ ______because more and more glucose and galactose stay in the lumen the osmotic pressure goes up, the _____ is secreted from the intestinal tract in order to compensate for the increase in osmotic pressure and it leads to diarrhea--> called ______ _____- because the diarrhea occurs because of the increased pressure inside of the lumen due to defective absorption of the glucose and galactose, and then when the glucose and galactose are not absorbed it causes diarrhea- and then the glucose and galactose will go all the way to the _______- Q in class: so rare that not all babies are tested for it, - in the colon bacteria are very happy, they get so much glucose and galactose and it causes them to ______--> when they ferment they produce _________ gas. In these children the colon produces lots of hydrogen gas causing _____, and not only that the hydrogen gas is absorbed in the _____ _____ goes to the lung and appears in the expired air so you can dictect the hydrogen in the expired air in lung, and therefore the presence of the hydrogen in the lung tells you the colon produces a lot of hydrogen- therefore if you have a patient with this and lung contains lots of hydrogen- it's produced in the _______! - although it gets eliminated in lung. How do you treat the patient? - now you cannot give ______, now lactose children do not tolerate- but you cannot change the breast milk into starch- b/c starch is made up of glucose. You cannot give glycogen- you can't give sucrose because made of glucose and fructose- and ________ is going to cause the problems, so the only treatment for children with the glucose-galactose malabsorption is to provide ________- because that is the only thing that does not care about the SGLT1 it uses ______ to get into intestine into blood and inside body fructose can be converted into glucose. Therefore you can provide fructose for the babies to treat- thereby avoid anything that can provide _____ and _____, but you can provide other things such as honey for fructose or fruit juices or coca cola. They won't get fat because they don't have any glucose- so the fructose is converted to glucose all of it to try to avoid the weight loss because they don't get any glucose and galactose in the diet. can be diagnosed with hydrogen in the lung air. How do you differentially diagnose that? -take the normal individual and measure blood glucose level, and then give an oral dose or any experimental carbohydrate--> give glucose then the glucose will be absorbed normally--> blood glucose will go up--> beta cells will secrete insulin --> it will bring down the blood glucose levels. Give one bolus of glucose to a normal individual- It will be absorbed, blood glucose will shoot up, and insulin will be secreted, then it will bring back the blood glucose level to the normal. And then to the same normal individual give sucrose - for example made up of glucose and fructose- also will be normal, nothing will happen you've given an equal amount of glucose either in the free form or in the form of sucrose blood glucose will go up and then it will be brought down to normal with the insulin. Same thing will happen with the lactose. Then if you look at the Hydrogen/H2 level in the air and look at the time, the hydrogen level will be very very low (time after oral dosing) the amount of the hydrogen will be normal level whether it is sucrose, glucose, or lactose. but what will happen in an individual with the glucose galactose malabosorption? Check the BG level, and then give glucose to that individual. When you give glucose, it's the normal level of glucose and it will remain the______- because glucose cannot be absorbed (flat line) - give an oral does of glucose and it will not increase blood glucose levels- see the same thing for_____, ________, and _______. What happens when you test for hydrogen? - it will be much ______, whether it is the glucose, galactose, or sucrose. Anything that contains glucose or galactose will increase the _________ production in the colon and it will appear in the lung and it will not increase the blood glucose level, and therefore you can diagnose this as ________-______ malabsorption.

neutral cationic

Hartnup disease: This is due to genetic defects in a transporter that is responsible for the intestinal and renal absorption of ________ amino acids (e.g., tryptophan, phenylalanine, leucine, etc.). But intestinal and renal absorption of cationic (arginine, lysine), anionic (aspartate, glutamate), and imino acids (proline) is not affected. The disease is associated with decreased plasma levels of tryptophan, leading to nicotinic acid (niacin) deficiency, manifested as pellagra (dermatitis, diarrhea, and dementia). The same neutral amino acids, which are not absorbed in the intestine in these patients, are absorbed normally when provided in the form of small peptides (for example, absorption of leucyl-tryptophan is normal in the intestine) because of the participation of the peptide transport system. The disease is benign in developed countries, but has serious clinical consequences in third world countries because of dietary protein deficiency. There is no protein malnutrition in Hartnup patients in developed countries. Cystinuria: This is due to genetic defects in a transporter that is responsible for the intestinal and renal absorption of __________ amino acids (lysine, arginine, ornithine, and cystine). But, intestinal and renal absorption of neutral and anionic amino acids as well as imino acids is normal. The primary clinical problem in the patients is the risk for kidney stones consisting of cystine. Plasma levels of cystine or cysteine are normal. The same cationic amino acids, which are not absorbed in the intestine in these patients, are absorbed normally when provided in the form of small peptides (example, glycyl-lysine or arginyl-lysine). The risk for kidney stones is the same in developed or third world countries. There is no protein malnutrition in developed countries.

iron hepcidin

Hemochromatosis is an inherited disorder of _____ absorption resulting from a greater than normal absorption in the intestine. Defects in five different genes have been shown to cause hemochromatosis, and all these five genes encode proteins that are involved in iron homeostasis. The gene HFE (i.e., histocompatability antigen involved in FE homeostasis) is defective in ~85% of patients with hemochromatosis. Irrespective of the gene defect, circulating levels of __________ are reduced in this genetic disease. Hepcidin is a iron-regulatory hormone, secreted primarily by the liver. This hormone works on the duodenum and reduces the intestinal absorption of iron. Therefore, reduced levels of this hormone in hemochromatosis increases iron absorption in the intestine.

80 amino acid transporters PEPT1 proton dipeptides and tripeptides peptidases PEPT1 promiscuous antibiotic B-lactan amino acid water small peptides amino acids intracellular peptidases tetrapeptide tri and dipeptides

How do you absorb the protein digestion products: -for this just remember the figure- the picture may be overwhelming so just think about the one he draws. -you have intestinal cell known as enterocyte: in lumen you get free amino acids and small peptides - the protein digestion does not go to completion in the lumen- therefore yu get dipeptides and tripeptides and free AA also. but the Dipeptides and Tripeptides constitute almost like ____% of the amino acids coming from the dietary protein. and the free amino acid only _____% and the free amino acids are absorbed via selective transport system called ___ _ ____- there are dozens of them responsible for transporting the free AA from the intestinal lumen into the intestinal cell. -Whereas the dipeptides and tripeptides are absorbed by a peptide transporter _______- peptide transporter 1- can transport the dipeptides along with the _______- a proton coupled transport system- (strange because most of the proton coupled active transporters have been described only in bacteria- something new for the mammals) - this one was the the first one described that is a proton coupled transport system in mammalian cells. he discovered this! That is the major route of absorption of protein digestion products- mostly because 80% of Amino Acids are present in the form of _________ and _______, and the free AAs only 20%, and then inside you get the AA and DP/TP and then they are acted upon by intracellular _________- an enzyme that hydrolyzes dipeptides and tripeptides- and the intracellular peptidases act on these to produce free AAs--> now the digestion is complete. because now the digestion resulted in the form of only elemental form of free AAs- which are then taken up into the blood by Amino Acid Transporters in the basolateral membrane what to remember: ******* - the brush border membrane of the enterocyte expresses _______- is responsible for the predominant absorption of the protein digestion products, it's a proton coupled transport system - there are about 20 diff amino acids, but there are so many amino acid transporters which are responsible for reaborption of free Amino Acids. but if you have 20 AAs- how many different dipeptides can you get? -400!!! (20 x 2) because you can assimilate one AA with the 20 other AAs--> then how many tripeptides? 8000, how many transporters do we have? only 1!! PEPT1- responsible for transport of 400 chemically diff dipeptides and 8000 chemically different tripeptides. the most ___________ transporter- it doesn't care, as long as it looks like a peptide it transports it- that's why it's a very good drug target because any ________ that you take for bacteria infection orally - how does it get absorbed? using PEPT1- because many antibiotics are _________ antibiotics many of them and the B-lactam antibiotics look like peptides, they are not typical peptides coming from the protein, and that is enough for PEPT1, so it grabs it transports it into the blood, and therefore the PEPT1 is very important for pharmaceutical companies and drug delivery. and if you take a certain drug like acyclovine- not actually absorbed because it is a nucleocyte and therefore the water availability is very low. and what they do to increase the water bioavailability is add an ______ _____ to the acyclovine by covalent bonding called ValAcyclovine- contains valine, the AA attached to that, now all of a sudden water bioavailibility is 10x better b/c acyclovine coupled with an AA valine looks like a peptide in terms of size and structure because you are putting an amino acid with that and now the PEPT1 doesn't care and it absorbs the ValAcyclovine and therefore you can increase the _______ availibility by targeting the peptide transporter. He wants us to remember the protein products are absorbed predominantly in the form of ___ ___ from the lumen into the cell. But how do they appear in the blood- in teh form of free ____ ____- because of intracellular digestion- _____ ______ cleave the dipeptides and tripeptides and produce free amino acids which get into the blood***********. Therefore if you ahve a surgical patient and you want to give an alimentation nutrition, water alimentation, when you give it you want to increase the amino acid nutrition of the surgical patient what is the form with which the most optimal one- if you give free amino acids it won't be good- because only 20% of these are absorbed. If you give big amino peptides like ________, pentapeptide it won't be absorbed but what is absorbed from pept1 has to be _____ and _________, anything bigger than that will not be absorbed. Therefore, any surgical patients when they want to be given amino acid nutrition they don't prefer to give the elemental amino acids, they mix it up with dipeptides and tripeptides to increase amino acid absorption due to the role of protein digestion products.

DUODENUM Calcium Binding protein calbindin Calcium CaATPase Calcium binding protein Calbindin Calcium NaCa intestine

How does it regulate Calcium Homestasis- remember this figure****** where is calcium absorbed in the intestine? __________(where most of the calcium is absorbed just like the iron and folic acid) and the calcium absorption in the duodenum occurs using this test. You have Ca2+ in the diet, and it goes into cells through _______ _____ _____- present in the brush border membrane of the enterocyte in the duodenum, and that enterocyte binds calcium and then the calcium comes inside and then it binds another protein called _______ inside of the cell (protein which binds calcium) - binds calciumfrom the BBM and brings the calcium to the other side of the cell and then calcium is extruded from the basolateral membrane into the blood through the _______ pump- which uses ATP as the driving force where it gets hydrolyzed and produces ADP and Pi, so it is also called _________ and it pumps the calcium out of the cell. Why do you call it a pump? Ca in the cell is normally around 1 uM concentration, and in the blood it is very high around 200-3000 uM and so you need ATP to drive the calcium against it's driving force. NaCa exchanger also but don't worry about it. So now you have four proteins involved in calcium absorption: -_________ in the brush border membrane -_________ in the intestinal cell -________ pump in the basolateral membrane -________ exchanger in the basolateral membrane and all four of them are Vitamin D dependent genes: when the intestine is acted upon, the hormone form of vitamin D 1,25 ---- it induces the expression of all 4 proteins, and that will increase the absorption of calcium in the intestine. and therefore you have to remember******, that vitamin D plays a very important role of calcium absorption in the intestine and also plays a role in kidney and bone, but mostly __________.

80-90 cholesterol monoglycerides Free Fatty Acids Brush Border Membrane transporters Triglyceride cholesterol ester phospholipid chylomicrons lacteals chylomicrons B-lipoprotein apo-B48 monoglycerides and fatty acids Endoplasmic reticulum MTP apoB48 chylomicrons ApoB48 chylomicrons A beta-lipoproteinemia fat chylomicrons fat soluble vitamin E

In addition to the triglyceride- which is the major form of dietary fat- almost ___-___%, but a little bit of dietary fat contains phospholipids and cholesterol and they all get digested-- don't worry too much about these things because they are a minor component. -Once they get digested, then what happens in the lumen , you get free _______ and then you get _______ and then you get ___ ___ ____- all of them are lipid soluble, and still you made them - you broke them down from the dietary fat to produce cholesterol, FAs and monoglycerides but again all of them are lipid soluble and water insoluble, so they diffuse across the ______ _____ ______, except cholesterol for reasons not shown- there are specific ______ for the cholesterol whereas the monoglycerides and fatty acids just cross the lipid bilayer by diffusion. Once they go into the Jejunal Enterocyte, they are reassembled again! ________ is resynthesized, ___ __ is resynthesized, ________ is resynthesized. - we have no idea why we break them, take them inside, and reform them- because they are all lipid soluble so why cant we just take them in their lipid form as Cholesterol esters/ phospholipids. etc and put them into the intestine, he has no clue. therefore they are broken down, get into cell , reassembled in the cell, never made any of it water soluble. Once they are made, they are assembled into macromolecules known as ________- chylomicrons is the end product big macromolecule which carries the triglycerides, phospholipids, and cholesterol esters. and this chylomicron, since it's a big lipid soluble macromolecule does not get into the portal blood-- it gets into the _____, goes into thoracic duct, that after a big, fat meal--> if you take plasma of your blood it will look milky mainly because there are so many _______ in your blood that it is not clear but of milky nature. When you spin it down, you get this milky deposit on top of the tube. and that tells that the chylomicrons contains all of those things, and then the chylomicron is availible from every tissue in the body without any preferential treatment from the liver. And then we have a genetic disorder with the lipid digestion known as A-beta-lipoproteinemia: Chylomicrons consist of a component known as _____________- which is nothing but a protein that contains lipids (like triglycerides, phosphlipids, etc) and the apoprotein without the lipid component is known as _____- 48 is the molecular size of the protein in kDa48- is the protein. The apoB-48 is responsible for taking the triglyceride synthesized in the intestine - triglycerides are broken down to the lumen to ____ and ___ ____. They diffuse into the intestinal cell across the brush border membrane. They are reassembled into triglycerides in the ____ _____and the triglyceride made within the lume of the ER has to be made availible for the protein to bind. For that you need a transporter called the ______ and the MTP is known as microsomal triglyceride transfer protein, and the protein is emulsed in order to assemble the triglyceride to the _______ and when ApoB48 gets loaded with the triglyceride, ______ are made- they carry all of the lipid digestion products and the fat soluble vitamins into the lacteal and into the systemic circulation. So what will happen if there is a genetic defect in the gene coding for MTP- If there is a genetic defect then the Triglyceride assembled in the ER cannot be loaded onto _________ , therefore you cannot make beta lipoprotein, if you don't make the beta lipoprotein you cannot get _____, and therefore there will be a problem with the digestion of the dietary fat. Because chylomicrons cannot be assembled and therefore the dietary fat cannot be absorbed in the gut, and therefore ___ ______--_______ leads to defective absorption of dietary fat. so what would you expect to see inthis patient? --> they will not be able to use fat as an energy source, and more importantly they will all suffer from deficiency of _____ soluble vitamins: A, E, D, and K-cannot be absorbed, now they don't need MTP, but _________ are needed to take the fat soluble vitamins from the intestine into the peripheral blood for the other organs and the chylomicrons are not made in this patient- therefore the primary symptom seen is actually ___ ____ _____ deficiency and only treatment for most of the symptoms are due to vitamin _____ deficiency for some reason. b/c even though but vitamin E deficiency and therefore patients are treated with the Vitamin E.

dinitrophenol hypoxia ouabain phlorizin Na+-independent jejunum

In the intact cell, glucose transport is inhibited by metabolic poisons such as ___________ (ATP synthesis is reduced), ______(ATP synthesis is reduced), __________ (Na+-K+-ATPase is inhibited) and ________ (it blocks the binding of glucose to its binding site on the Na+-dependent glucose transporter). Glucose, galactose, and fructose (all three monosaccharides) leave the intestinal cell across the basal-lateral membrane to enter into the blood. This process occurs via a facilitated glucose transport system designated as GLUT 2. The transporter is not active and is ___ ___________. Absorption of all three monosaccharides is greater in__________ than in the ileum.

Lactase lumen osmotic diarrhea colon hydrogen blood glucose SGLT1 low hydrogen

Lactose intolerance: -not allergic to lactose -just cannot digest and use the lactose- the glucose and galactose present in the lactose -In these ppl, when they take lactose, it cannot be hydrolyzed because they have deficient enzyme: _____- the only enzyme in the intestinal tract that can hydrolyze lactose (b/c we talked about 3 enzymes: sucraze- isomaltase, maltase-isoamylase, and lactase- the only one which can hydrolyze lactose) -Conversion of Lactose into glucose and galactose cannot occur because enzyme is deficient, lactose level goes up in the________ because it cannot be digested in the intestine, when it goes up it causes osmotic pressure to increase- water increases- it causes diarrhea called ______ _____, so the patients with lactose intolerance also will have similar problem with intestinal tract. cannot digest the lactose- so the lactose goes to the _______, the colon bacteria hydrolyzes lactose ferments it and produces ___________, and they will suffer from abdominal distention and flatus, and there will be more hydrogen in the ________. How do you differentiate a patient between glucose-galactose malabsorption and patient with lactose intolerant? very easy - mainly because all the things you saw with g-G malabsorption, the blood ______ will remain the same whether it is glucose, galactose, or sucrose, and the hydrogen test will be higher in a patient given glucose, galactose, or sucrose - b/c the defect is in the absorption of g and G. -In Lactose intolerant patient the results will be completely different. When you give glucose the blood glucose will be normal, because there is no defect in ____ - glucose will be absorbed normally, hydrogen test will be very_____. What happens when you give sucrose- made of glucose and fructose- does not require lactase- this will be the similar thing. But you give lactose to that individual, the glucose line will be flat, because the lactase is deficient in the individual so only the lactose cannot be digested not the sucrose, therefore the lactose will not increase the BG level, and you give lactose it will increase the breath _________. Mostly because this is the only one dietary component which is the culprit. need to know this*** -not for the test: The ppl who suffer from the lactose intolerance feel bad because they cannot drink milk or eat icecream, or have any dairy products, but don't feel bad because the ppl who tolerate lactose are the abnormal ppl, and the mutants who can drink liters of milk without any abdominal problem- mainly because you take any other animal primates, which depend on milk as the primary infant formula for the lactose as the source. What happens is when you look at the lactase level, it stays very high until weaning period, and therefore until the baby is actually sucking the milk depending on the lactose, lactase activity is very high because it's physiologically important lactose is the primary carbohydrate source in the infant. Then once the weaning occurs you don't get any more lactose, and therefore your body doesn't need lactase and we have been programmed in order to reduce the lactase level because why do you want an enzyme which has no physiological function- therefore we are not supposed to drink milk after the weaning period. Therefore we all have reduced lactose activity because lactose is not supposed to be the diet all along your life. Therefore all of us are suuposed to be lactose intolerant, but in some ppl they have a mutation in the gene. These are the people which are lactose tolerant- the mutants.

portal blood amino acids and monosaccharides liver portal blood Lacteals thoracic duct subclavian systemic liver liverthoracic AEDK

Lipid digestion and absorption: Anything water soluble gets absorbed into the ______ ______ - true for carbohydrate and protein digestion because ____ ____ and _____ are water soluble, they get absorbed into the portal blood and it goes to the _____. The liver is the first to sort what is coming from the intestine via the _____ _____. Whatever is left goes into the systemic circulation, then only the other tissues can have a shot at it. That is not true for the lipid digestion products- because these are water insoluble!! and the water insoluble products of the lipid, dietary fat does not get into the portal blood- only water soluble products can get in there. Therefore the lipid digestion products enter into the _______, it goes into the lymphatic system, and in the lymphatic system the ___ __gets all of the absorbed fat digestion products from the intestine because lacteals they form the thoracic duct and the thoracic duct brings all of the stuff that the digestion of fat and the fat soluble vitamins- then they go into the ____ vein and dump all of the components into the subclavian vein b/c the thoracic duct empties straight into here--> then it goes into the ____ circulation. When it goes into the systemic circulation, the _____ does not have any preferential treatment when it comes to dietary fat digestion products b/c when it;s in systemic every organ has an equal shot at what is coming from the systemic blood. remember*****water soluble absorption products go to the _____ first then to the rest of the digestive organs. Fat digestion products do not have any preferential treatment for the liver, because it goes through the _____duct into the systemic circulation so every organ has an equal shot at what is coming from there. When I say fat soluble, I am including fat soluble vitamins also= __, __,__,__ are absorbed via the thoracic duct and not the Portal Blood, whereas all other water soluble vitamins like vitamin C or biotin, or pantothenic acid, or B12, or folic acid, they all end up in the portal blood and go to the liver. so remember between the protein and carbohydrate digestion products where do they end up and the lipid products where they end up.

stomach intestinal lumen bile acids hepatocyte micelles lipase bile acids lipase pancreatic duct triglycerides 1 and 3

Lipid digestion: go through quicker cause all you have to know is: -the fat which is water insoluble has to be solubilized in the _______, and in the ______ _____. Therefore, they are actually converted into emulsified, because all fat droplets are to be emulsified broken into little fat droplets and that it done by the mechanical agitation of the stomach and intestinal contraction. and then the big fat droplets are broken down into small and they are emulsified which requires a detergeant an the detergeant is the ____ ____ - which are secreted by the _____ into the bile duct and then the bile acids now act on the fat droplets and emulsify them. After emulsification and then you form ________ using the bile salts. and the micelles are now acted upon by the pancreatic enzyme known as ______. -and therefore the first one is the emulsification- the mechanical break down of big fat droplets into smaller ones. -next one is micelle formation which require detergeants which are __ ____ -then you have enzyme hydrolysis and the enzyme is known a the _____- the predominant enzyme responsible for the dietary fat, and the lipase comes from the pancreas! and the lipase is then secreted into the _____ ____, comes into the lumen and acts on the major lipid component in the dietary fat. You are taking a lot of normal dietary fat in a regular diet. what is the predominant form in which the fat exists in the diet--> ________ - the glycerol where all 3 hydroxyl groups are esterified with the three different fatty acids. That is called triglycerides, the predominant form in which we take dietary fat. The is the bottom one, the blue one is the glycerol and the three different red ones are the three different fatty acids attached together and the pancreatic lipase acts on that and then releases the fatty acid from the carbon atoms ___ and ___- leaving the fatty acid attached to the middle carbon atom- and that is now called a monoglyceride (when only one FA is attached) These are the products of Pancreatic Lipase action actually on the dietary fat.

facilitated diffusion actively Na+ and glucose electrogenic Galactose

Luminal and membrane digestion of dietary carbohydrates produces glucose, fructose and galactose. Fructose is absorbed by _______ _______. It is not an active process and hence no energy is required. Glucose and galactose are _______ transported into the mucosal cell by a common transport protein. The energy for the process is provided by an electrochemical Na+ gradient. The glucose carrier has binding sites for ______ and _____________. When the carrier binds both Na+ and substrate, it translocates across the membrane. Na+ and the substrate are released into the cell and the unloaded carrier comes back to the original position to start the transport cycle again. Stoichiometry between Na+ and glucose is 2:1. The transport process is _________ i.e. transport of glucose and Na+ via the carrier results in the transfer of positive charge across the membrane. Thus, both the electrical as well as the chemical components of the electrochemical Na+ gradient provide energy for glucose transport. The process is called Na+-glucose cotransport (symport). ___________ shares the glucose binding site. Even though the electrochemical Na+ gradient is the direct energy source for glucose transport, ATP is ultimately necessary for the transport because it is the ATP hydrolysis via the Na+-K+-ATPase, which generates the electrochemical Na+ gradient.

salivary stomach pancreas apical

Luminal digestion is due to enzymes secreted from _______ glands, ________, and _______ into the lumen. Membrane digestion is due to enzymes associated with the _______ (brush border or microvillous) membrane of intestinal enterocytes

brush border disaccharides starch and glycogen

Membrane digestion Membrane digestion of carbohydrates is catalyzed by intestinal _______ _______ carbohydrases. The substrates are ingested ___________ (sucrose, lactose) and the products of digestion of _____ and ______ by salivary and pancreatic amylases (maltose, maltotriose, a-limit dextrins).

B3 nicotinamide adenine dinucleotide (NAD+) nicotinamide adenine dinucleotide phosphate (NADP+). pellagra tryptophan

NIACIN Also called vitamin _____. The term niacin refers to both nicotinic acid and nicotinamide. Niacin is the precursor of the coenzymes ________ and its phosphorylated derivative ________ Function: 1. Redox reactions: These reactions involve the transfer of two electrons and two protons. Both NAD+ and NADP+ accept two of the electrons and one of the protons, the other proton remains in solution (NADH/NADPH + H+). NAD+ is used as an electron acceptor in catabolic reactions and in the generation of ATP; NADP+ is involved in biosynthetic reactions. 2. Donor of ADP-ribose group: NAD+ acts a substrate for poly(ADP-ribose) polymerase in the ADP-ribosylation of proteins. Nicotinamide is released. The enzyme is involved in controlling the repair of DNA. Also, a substrate for ADP-ribosylation of some proteins by bacterial toxins such as cholera, pertussis and diphtheria NAD+ serves as donor of an ADP ribose group for the synthesis of cyclic ADP-ribose. Similar to IP3, cyclic ADP ribose stimulates the release of Ca2+ from intracellular storage sites. 3. Pharmacological use of niacin: Niacin inhibits lipolysis in adipose tissues and hence used in the treatment of hyperlipidemia; acts through a G-protein-coupled receptor. Deficiency: Deficiency causes _________. Symptoms of pellagra progresses through dermatitis (rough, scaly, pruritic skin with erythematous erruptions, especially in sun-exposed areas), diarrhea, dementia (confusion, memory loss), (the "three D's") and, eventually, death. Deficiency is seen in alcoholics with poor nutrition, and in patients with Hartnup disease and carcinoid syndrome. Source: Limited amount synthesized in the body from the metabolism of _____________. Other sources: mainly seafood, nuts and meats. RDA is 19 mg/day.

NaH+ Cl-HCO3- bicarbonate chloriduria ClD NaCl H+ and HCO3- NaH Cl-HCO3- electroneutral ELECTRONEUTRAL NACL cyclic AMP inhibits Na and Cl cyclic AMP CHOLERA Cyclic AMP cAMP cyclic AMP

Next we talk about NaCl absorption: -occurs using two different transporters: 1. ______ exchanger- transports the Na+ in and the H+ out, so the sodium proton exchanger is present in the brush border membrane- seen in pic in top cell 2. _________ exchanger-Cl goes in and HCO3- goes out into lumen b/c ________ is excreted in the intestine as well as in the colon and the Cl-HCO3- exchanger is responsible for that. In the picture it's written as ClD- which stands for the gene which causes your disease called _________ - a genetic disorder in which the chloride bicarbonate exchanger is defective - when it's defective chloride cannot be absorbed and therefore they lose chloride actually in the fecal material- known as chloriduria and the gene is called ______ but functionally it's known as Chloride bicarbonate exchanger. and the Cl-HCO3- exchanger when you combine together-> Sodium is absorbed and Chloride is absorbed into the cell and you get _______ inside of the cell. In the lumen you get ___ and ______ and they combine to make carbonic acid and they can be split into CO2. Therefore these two exchanges ____exchanger and _________ exchanger , together mediate the absorption of NaCl. Now when you look at the NaH exchanger, there is one positive charge going into cell and another positive charge going out of the cell, look at the Cl-HCO3- exchanger- has one negative charge going in and one negative charge going out, both are __________ - not electrogenic- electroNEUTRAL- no change in depolarization of membrane potential therefore together it is known a __________ __________ ABSORPTION- how NaCl is absorbed into the small intestine*******talking about two different transporters: NaH and ClHCO3 -and these two transporters are regulated by _____ ______inside of the cell- very important regulator - it______ both the NaH exchanger and ClHCO3 exchanger. Therefore whenever the cyclic AMP level goes up in the cell (higher in an individual than normal ) it's going to block both of the exchangers and ____ and _____ will not be absorbed. and therefore, ______ _____ blocks the electroneutral NaCl absorption in the intestine because it blocks both exchangers. If the NaCl is not absorbed then you get osmotic diarrhea--> because the increase in Na and Cl in the lumen cause an increase in osmotic pressure and increased water reabsorption--> what happens in __________!!!- caused by a bacteria that produces a toxin that acts on the intestinal cells and increases ________ ______. Therefore cholera leads to increase in _______ it blocks NaCl reabsorption and causes severe diarrhea. -Same thing happens in another disease known as Traveler's Diarrhea. Go from here to 3rd world countries, and most of the time it is from an E.coli strain known as enterotoxigenic e.coli. (entero= effect on small intestine) toxigenic (produces toxic effect on aka produces pathology ) , so the e.coli strain that produces a toxic effect on the intestine produces travelers iarrha and also increases _______ _____- goes up and causes diarrhea.

starch sucrose lactose polymers glucose linear a-1,4 a- 1,6 glycogen branches disaccharide Fructose and Glucose disaccharide PFK1 citrate and ATP fat PFK1 feedback

Next we talk about what are the various nutrients and how they get absorbed: Carbohydrate: -the dietary carbohydrate is primarily made up of _______ ( glycogen if you're a meat eater) - constitutes about 50-60% of dietary carbohydrate -_______- table sugar/ regular sugar we use. -________- milk sugar -fructose -these are the important constituents of the dietary carbohydrates. Whether it's starch or glycogen-- all of them are glucose ___________, They contain thousands of glucose residues attached together, and therefore the only carbohydrate/ polysaccharide present in starch or glycogen is _________. Then the starch can come in two different forms: -amylose and amylopectin- both are presence in dietary starch, when you say amylose- a ________ polysaccharide of the glucose, contains glucose residues in the linear fashion- like these thousands of glucose residues attached together just in the linear fashion, and made up of only one type of glycosidic bond between the glucose and the next glucose- that is known as the _____ linkage (the carbon atom 1 of one glucose is attached to the carbon atom 4 of the next glucose) and the isomeric form is the alpha rather than beta. The a-1,4 linkage is responsible for the glucose polysaccharide in amylose. -In amylopectin - it contains the linear portion just like amylose, BUT it also has branches - made up of _______ linkages, therefore amylopectin has a-1,4 and a-1,6 linkages because the branch point is made up of a-1,6 and the linear is made of the 1,4 linkages. -And Amylopectin is very similar to __________because glycogen is also your branched glucose polysaccharide. The difference between glycogen and amylopectin is that there are more ________ in glycogen than in amylopectin, otherwise they are exactly the same- made of glucose with both linkages -Sucrose is a ______________ made of __________ and ___________ -Lactose is a ____________ made of Glucose and Galactose -these are very important - remember these two*** -we have a lot of fructose in our diet- especially in the soft drinks - all contain high fructose corn syrup- added to sweeten coke- contain high levels of fructose- lot's of interest between fructose levels and obesity- increased fructose means increased weight - because it goes straight into fat -comparing fructose versus glucose, when you take a lot of Glucose--> make acetyl CoA, and the carbon skeleton for this can be used for the fat biosynthesis - take more glucose and get more fat synthesis- but this fat synthesis from glucose is a regulated process because of bottleneck n glycolysis called ________- highly regulated protein, regulated by ______ and ______- which inhibit that enzyme. Therefore if cells are loaded with citrate- it can inhibit PFK1 and then prevent the process of the glucose into the fat. And the Citrate is the metabolic intermediate in the _______ biosynthesis because citrate is made within the mitochondrial matrix comes out of the matrix in the cytoplasm, is acted upon by an enzyme called ATP citrate lyase and then breaks the citrate--> produces Acetyl CoA which can be converted into fat in the cytoplasm (b/c fatty acid biosynthesis occurs in the cytoplasm not in the mitochondria) Therefore when the cytoplasm has a lot of citrate that gives the signal for fat biosynthesis, that citrate prevents that PFK1 so that there is no more Acetyl CoA production in the mitochondria. Therefore the synthesis of the fat from the glucose is feedback regulated- if there is more citrate it prevents the metabolism of glucose to provide the carbon skeleton. -That is not the case for fructose! because Fructose enters glycolysis after the level of ________ because fructose goes through and then it produces dihydroxyacetone phosphate and the glyceraldehyde and these are the two metabolites that enter glycolysis and make acetyl CoA and this glyceraldehyde and the DHAP come two or three steps later of the PFK1- therefore the synthesis of fat from fructose is not regulated by ________ regulation. SO the more fructose you take the more fat biosynthesis, The more glucose you take, yes you will get more fat, but in a restrained manner. In a regulated manner. - why you have to watch how many drinks you have made of HFCS- can lead to major fat production in body. -So these are the major constituents in the diet, the carbohydrate, and how is it actually digested

JEJUNUM glucose, galactose and fructose SGLT1-Sodium coupled Glucose transporter 1 SGLT2 SGLT1 diabetes 2 reabsorbed glucose or galactose electrogenic sodiums glucose depolarizes Active diet intestinal secretion, bile, or pancreatic lumen accelerate potential sodium Fructose GLUT5- known as Glucose Transporter 5 - facilitative GLUT2 facilitated diffusion NaKpump sodium down Oubain digoxin Calcium glucose fructose ' monosaccharides jejunum

Next, absorption of dietary carbohydrate products and protein digestion products. All you need to know is this figure for the absorption of carbohydrate products!!*** -All carbohydrates are absorbed in the __________- primary site, and the brush border cell is made up of the brush border membrane, the basolateral membrane. BBM on lumen side, and BL membrane on blood side, and in the lumen you have ______, _____, and _______ at end of digestion of carbohydrates- using luminal and membrane digestion. Now, How do these 3 monosaccharides get absorbed into the intestinal cell and into the blood? -the glucose and galactose are absorbed via a specific transport system known as _______, a second one is ______ and is found in the kidney b/c we all have so much glucose in the blood, which gets filtered in the kidney, but normal ppl don't lose glucose in the urine, therefore the fructose glucose gets reabsorbed in the kidney, so you need a glucose transporter not only in the intestine but also in kidney. But the kidney is done by SGLT2 whereas intestine is known as _________. Because of this SGLT2 is becoming a major target for __________ ___- if you block this using an inhibitor, glucose is filtered but it will not be _________ back into the blood, it will be sent into the urine and you can keep glucose low in the blood. But SGLT1 is not a major target for diabetes 2 so far, when you block it your dietary glucose cannot be reabosorbed, but no one is looking at it. -SGLT1- what is in the intestine. It transports sodium along with ________ or _______- glucose and galactose don't transfer at the same time. It can transport glucose or galactose with sodium depending on availability of glucose and galactose. The SGLT1 is known as an _________ transporter - means when the transporter functions, it depolarizes the membrane. Now why would you think it was electrogenic- b/c glucose has no charge on the molecule -it's a neutral molecule. And SGLT1 normally transports 2 __________ and one ______, and therefore, it takes to positive charges from outside to inside the cell, because glucose is neutral but it goes with the two sodiums through a process called cotransport- they both travel at same time and it takes two positive charges. and since the inside is always negative like in any other cell- by bringing the positive charge it ________ the membrane- why it's called electrogenic. ________ transporter means it is an energized process- it needs an energy source- the energy source for this is the sodium gradient : sodium concentration is always higher outside than inside: 5-10mM and outside is around: 130mM, as you can see that is a 10 fold increase in the intracellular sodium versus the extracellular sodium, but the lumen is not blood- so where do you get all of the sodium in the lumen? comes from the ______ or gastric, salivary , _______, _____, or _______ secretion; Therefore, sodium is released into the intestinal lumen from the diet and from secretions and therefore hte sodium here is much higher in the _______ than it is inside, and that sodium gradient can provide a driving force for the glucose and galactose absorption. Not really the sodium gradient, the inside negative membrane potential also provides an energy source, for the absorption of glucose and galactose because inside negative membrane potential will __________ any transport process which brings a positive charge inside the cell. Because inside the cell is more negative so it wants to bring more positive charge for neutralization, and therefore the membrane _________ and the ________ gradient provide the driving force for the glucose and galactose absorption in the enterocyte. The __________________ does not go via SGLT1- that is important*** it is not accepted by a substrate by the sodium coupled glucose transporter. Whereas the fructose actually gets absorbed by another transporter known as _________it is a misnomer, this glucose transporter is actually a Fructose Transporter!!** we call it glucose transporter but the glucose and fructose are isomeric forms, and therefore the fructose is the substrate for the GLUT 5. The GLUT5 is not an active transporter- no energy source at all, no sodium gradient, no membrane potential involvement, and it is a simple __________ transporter- not active. And therefore now you have glucose, galactose, and fructose inside the cell with the function of SGLT1 and GLUT5. How do they get out into the blood?- using another transporter ________- the glucose transporter 2 expressed in basolateral membrane of enterocyte. GLUT2 cannot differentiate between glucose, galactose, and fructose, it can transport all 3 from the cell into the blood. It is _____ _____mechanism. That is the mechanism. How is the sodium gradient maintained- we have the ________ across the basolateral membrane- removes the sodium to out of the cell in exchange for potassium and then it uses the ATP as the driving force for that. And the sodium potassium pump in the basolateral membrane keeps pumping the sodium out of the cell keeping the sodium concentration inside the cell low, so that across the BBM you can have a ________ gradient. And therefore if you can come up with an inhibitor of the NaK pump, what would be the effect of the inhibitor on glucose absorption in the intestine- glucose absorption will go _______, b/c you need pump to make the sodium gradient, and if you inhibit the NaK pump the energy source goes down and glucose cannot be absorbed--> most famous inhibitor of NaK pump is ________ called Digitonin Didroxine which is used for the cadiovascular system, in order to increase the contraction force of the heart, they can use actually ________, and it is used in patients with defective cardiovascular function. Therefore, why it inhibits the NaK pump, it can increase intracellular _______ concentration in the cardiac muscle and increase the contraction force, and therefore Digoxin facilitates the contraction of the heart muscle- but when you take it-it has side effects that it can interfere with the _________ absorption in the gut- mainly because we are targeting the NaK pump in the cardiac muscle, but the Digoxin doesn't care whether it's present in the cardiac or small intestine- therefore you can inhibit glucose absorption in small intestine. but when you take digoxin it will not interfere with the _______ absorption, because fructose does not depend on SGLT1- therefore it does not depend upon sodium gradient, and therefore you don't care whether the sodium gradient is there or not the fructose is absorbed normally. And that's what you need to know for different pathways in absorbing glucose, galactose and fructose. -only ____________ are transported at the brush border -duodenum and upper______ have the highest capacity to absorb monosaccharides -5-10% CHO passes undigested to colon, metabolized by colonic eipthelial cells

Luminal lumen pancreatic starch and the amylopectin Enterocytes Sucrase- isomaltase maltase-Glucoamylase Lactase sucrase- isomaltase maltase/glucoamylase sucrase maltose glucose alpha 1,6 a-limit dextrin amylase branch maltose maltotriose Pancreas enterocyte glucose and galactose and fructose

Now what are the enzymes that hydrolyze sucrose lactose and any other carbohydrate? - when you look at enzymes here: the process mediated by Pancreatic Amylase is known as _________ Digestion - means the digestive process occurs within the intestinal _________ using the enzyme which comes from the __________ secretion. Therefore it is known as the lumenal digestion, whereas the rest of the digestion of carbohydrate is occurring by a process called membrane digestion- process where the digestion occurs in contact with the membrane. What is the membrane we are talking about? -now we are in the Jejunum, because the pancreatic duct brought the amylase, it acts on the ______ and ___________ and then we are in the lumen of the jejunum. Jejunum is made up of these cells called ___________- the functional cells of the Duodenum, Jejunum, and Ileum and the enterocyte is the absorptive cell- contains something that is called a brush border membrane- looks like a brush because it's a highly convoluted plasma membrane- that part of the membranes. Both the basolateral and BB membranes are part of the plasma membrane of Enterocyte- but they are like day and night in terms of function and protein composition. BBmembrane contains different types of proteins, and the basolateral membrane contains different types of proteins. Therefore, we call this cell a polarized cell because part of the membrane is different from the rest of the membrane, so we call the enterocyte a polarized cell. And therefore the BB membrane is in the lumen, and the Basolateral membrane is on the blood side. -and this membrane contains 3 enzymes necessary for the hydrolysis of the carbohydrates. The 3 enzymes are: 1. _________- __________ 2. _________- _________ 3. ________ -there is no separate enzyme known as maltase in the intestine-- the maltase is the enzymatic activity which is associated with the _______________ and the ___________, and therefore, just remember it's not very important, but there is no maltase separate enzyme, but the maltase is the enzyme which hydrolyzes maltose and that enzyme activity can come from the sucrase isomaltase as well as the maltase-glucoamylase. and here the ________ part of it is responsible for hydrolyzing sucrose and also maltose. So the sucrase part of the sucrase isomaltase can hydrolyze ________ and sucrose. If it hydrolyzes maltose it produces _________. If it hydrolyzes sucrose, it produces glucose and fructose. Therefore the same enzyme sucrase can act on maltose and sucrose. The isomaltase is very important, because that is the only enzyme which is careful about hydrolyzing the _____ _____ linkage - and the a-1,6 linkage is found in the _____________, and the a-LD is produced by ________ after acting on glycogen and amylopectin, and that a-limit dextrin is hydrolyzed by the isomaltase which hydrolyzes the a-1,6 and an removes the ________ point, and then you can produce the glucose, and the maltase glucoamylase acts on ________ as well as the _________. Finally lactase- responsible for hydrolyzing lactose to make glucose and galactose. The point to remember is these 3 enzymes do not come from __________******These are the membrane bound enzymes associated with the brush border membrane of the _________. Therefore this is the membrane that contains these enzymes- integral membrane protein, therefore when maltase comes into contact with the enzymes it will be broken down and that is why it is called membrane digestion- b/c the digestion process occurs in contact with the membrane and we call it a membrane digestion. Therefore at the end of all of these things, carbohydrate digestion leads to ______ ______ and ______- the 3 monosaccharides present in lumen after digestion of carbs- this means that the carbs present in your diet is completely digested into the elemental form: monosaccharide- glucose, galactose, and fructose. These are end products of carbohydrate digestion. It requires both luminal digestion as well as the membrane digestion.

pyridoxal phosphate amino acid glutamate decarboxylase (decreased production of GABA) Microcytic anemia alcoholics isoniazid, penicillamine protein

PYRIDOXINE Also called vitamin B6. Three forms- pyridoxal, pyridoxine, and pyridoxamine. Biologically active coenzyme is _________ _________, which is tightly attached to the enzyme. Function: Mainly involved in _____ ______metabolism through transaminations, deaminations, decarboxylations, condensations and transsulfuration. Pyridoxal phosphate serves in the transfer of inorganic phosphate to the glucose units on glycogen as a cofactor of glycogen phosphorylase. Most of the body's pyridoxine (70-80%) resides in the muscle bound to glycogen phosphorylase. Deficiency: Most of the problems associated with pyridoxine deficiency arise from the impairment of _____ ______. The symptoms include depression, confusion, and sometimes convulsions. _____ _____ may result due to reduced hemoglobin synthesis (decreased heme). Deficiency usually seen in ________, infants fed with formula low in the vitamin and TB patients being treated with ________, _________. Toxicity: Intake of greater than 2 g/day-neurological symptoms: difficulty in walking, tingling sensations in the legs and soles of feet. Source: Wheat, corn, egg yolk, liver and meat. RDA is 2.0 mg and is increased by high intake of ________.

active Colipase acinar procolipase inactive enteropeptidase colipase protein trypsinogen procolipase

Pancreatic Lipase: The Lipase produced by the Pancreas is in the ______ form (not like trypsinogen, not like the pepsinogen from the stomach) but lipase itself is active form, but it requires a cofactor--> _____- which is also produced by the pancrease- the _____ cells. and that colipase is produced as an inactive precursor called _____, which comes into the pancreatic duct and into the intestine. so even though lipase is in the active form, it does not have good bioactivity because the pro-colipase is in the ______ form, until the contents come to the intestine. There the procolipase is activated by __________ - the same enzyme that activates the trypsinogen also activates the procolipase then produces the active form of ______ which now combines with the lipase and increases this catalytic activity. And thereby, the enteropeptidase genetic defect not only affects the _____ digestion but also affects the fat digestion. Because enteropeptidase is needed not only to activate _____ but also to activate the _______, so an enteropeptidase defect can affect dietary FAT and PROTEIN digestion.

exocrine 1,4 a1,6 a1,4 glucose

Pancreatic amylase is a constituent of the __________ pancreatic secretion. It hydrolyzes the internal a _____ linkages of amylose resulting in maltose and maltotriose. In the case of amylopectin, pancreatic amylase cannot hydrolyze ______ linkage as well as ____ linkages near the branch points. Therefore, the products are maltose, maltotriose and a-limit dextrins. These limit dextrins contain an average of 8 glucose units and one or more branch points. No _________ is formed by the action of either salivary or pancreatic amylase on starch and glycogen.

active colipase 6-8 bile salts pancreatic phospholipase A2. trypsin pancreatic esterase solubilized bile salts

Pancreatic lipase This enzyme is secreted by exocrine pancreas in an _____ form rather than a zymogen. But it needs another protein called ____ for its activity. The colipase is also secreted by the exocrine pancreas, but as an inactive precursor called procolipase which is activated in the intestinal lumen by trypsin. Optimum pH for lipase ___-___. Pancreatic lipase acts readily on emulsified triglycerides, but only in the absence of ____ ____. Its activity is strongly inhibited by bile salts because these naturally occurring surface-active agents displace lipase from the lipid- water interphase. Colipase binds to lipase in a 1:1 molar complex and also binds to the bile salt covered triglycerides, thus anchoring lipase to its substrate. In addition to triglycerides, dietary fat contains small amounts of phospholipids and cholesterol esters. The major enzyme responsible for phospholipid digestion in the intestinal lumen is ____ ____ ___ It is secreted as prophospholipase A2 which is then activated in the lumen by ____. It hydrolyzes phospholipids at position 2 to yield lysophospholipids and free fatty acids. It has an absolute requirement for bile salts. Cholesterol esters and, to some extent, monoglycerides are hydrolyzed by a _______ _____, releasing cholesterol, glycerol, and free fatty acids. Unlike the end products of carbohydrate and protein digestion, the end products of fat digestion should be _______ first before they can be absorbed. This is achieved by formation of micelles in the presence of ____ _____ (e.g. glycocholate, taurocholate). The water-insoluble fatty acids, P-monoglycerides, cholesterol, lysophopholipids and fat-soluble vitamins can be solubilized in this manner.

SGLT1 (fructose) glucose and galactose

Pathophysiology of Absorption Genetic defects in transport systems: Glucose-galactose malabsorption - defect in Na+-dependent glucose transporter (diarrhea). This transporter is known as ________. Any carbohydrate source in the diet will lead to diarrhea with a single exception _________. Starch, sucrose, lactose, glucose or galactose will lead to diarrhea and also in increased breath hydrogen levels. An oral load of glucose, starch, sucrose, or lactose will provide only a blunted response in blood glucose levels. Even though all the enzymes related to carbohydrate digestion are normal, the absence of SGLT1 leads to defective absorption of _________ and ________, causing the clinical symptoms.

Crohn's Zollinger-Ellison iron, calcium, and microcytic anemia secretin fat and fat-soluble vitamins (steatorrhea) glucose hydrogen

Pathophysiology of Digestion: Deficiency of digestive enzymes: Hereditary, pancreatic inflammation, cystic fibrosis, ______ disease, celiac sprue, tropical sprue, _____- _______ syndrome (gastrin-producing pancreatic tumor) Celiac disease: Gluten-induced enteropathy (wheat, rye, barley). When active, the disease affects primarily the proximal portion of the small intestine, thus leading to decreased absorption of ______, _______< and ________ _______. There is also decreased _______ production, thus leading to increased acid output from stomach. Deficiency of bile salts: Interruption of enterohepatic circulation (ileal resection, obstructive jaundice), bacterial overgrowth into small intestine, liver cirrhosis, hereditary defect in ileal bile salt transporter. These conditions lead to malabsorption of ____ and ___________. Lactose intolerance -deficiency of lactase activity (intolerance to milk and other dairy products), breath hydrogen test. An oral load of glucose will increase blood levels of glucose with no change in breath hydrogen levels; in contrast, an oral load of lactose will fail to increase blood levels of ________ (lactase deficiency; therefore no digestion of lactose and therefore no absorption of glucose/galactose from lactose) with a marked increase in breath ___levels.

antibiotics hypercholesterolemia Na+ cotransporters H+ cotransporters

PepT1 • A member of the solute‐carrier (SLC) superfamily. • Drugs undergoing H ‐coupled cotransport across intestinal brush‐border membranes include _______ (such as penicillin and cephalosporin) and drugs for ________, hypertension, hyperglycemia, viral infections, allergies, epilepsy, schizophrenia, rheumatoid arthritis, and cancer. • Immediately after birth, intestinal epithelial cells can absorb some peptides larger than three amino acids by transcytosis (4). This absorption of intact protein transfers passive immunity from mother to child and ceases by about the sixth month after birth. AAs are absorbed by ___ ___________, di‐ & tripeptidases are absorbed by __ _____________

active H+ Na+ Na+-H+ P-lactam

Peptide Transport Across BBB It is an _______ process. It is energized by an electrochemical _____ gradient. It is not dependent upon a _____ gradient. It accepts dipeptides and tripeptides as substrates. The H+ gradient across the brush border membrane is generated by the action of the _________ exchanger. Orally active ________ antibiotics are absorbed from the intestine via the peptide transport system.

25 luminal membrane intracellular lumen membrane glucose, galactose and fructose inside amino acids pepsin trypsin, chymotrypsin, elastase, and carboxypeptidases acinar proteolytic chewing pepsinogen stomach pepsin acidic activates proteins activity protein Pancreatic acinar Trypsinogen chymotrypsinogen ProElastase ProCarboxypeptidase A ProCarboxypeptidase B acinar neutral enteropeptidase enterocytes trypsin lumen small peptides outside dipeptides and tripeptides intracellular

Protein Digestion: -dietary protein about 100g- ____% comes from sloughed cells. and of course diet too. -proteins are digested in 3 different ways: 1. _______ digestion 2. ________ digestion 3. _________ digestion -remember the difference between carbohydrate and protein digestion*****: -> in carbohydrate, the digestion is complete outside of the cell because amylase can act in the _______, lactase, sucrase, isomaltase, maltase, glucoamylase can all act bound to the _______ but the action occurs outside and it can produce ______, _______, and ________. Whereas the protein digestion cannot be completed outside of the cell it has to be completed _______ of the cell!! Therefore there is luminal, membrane, and intracellular digestion leading to elemental form of protein: free _____ _____- produced inside cell after these 3 processes. -Enzymes responsible for lumenal digestion: -> _______- from the chief cells in the stomach, very important for protein digestion. -> pancreatic secretion- contains several proteins: known as_______, ______, __________ and ____________. - and these are the different enzymes produced by the pancreatic________cells. Acinar cells secrete the trypsin, CT, E, and CBP, and all of them come to the duodenum. The pepsin is a _________ enzyme- you don't want the chief cells to produce this in the active form. because the chief cells produce pepsin inside the cells before releasing outside. Before it gets released, pepsin will start _______ up the protein inside of the cell causing damage to the originating cell- b/c of that chief cells do not produce pepsin in the active form but do produce an inactive form _________- the inactive precursor is produced by the chief cells and sent into the ________ lumen, and then in the lumen the pepsinogen gets converted into ______- this conversion is mediated by an ______ pH- the protons are responsible for activation of pepsinogen. This process occurs in the gastric lumen- this is very ideal because the gastric luminal pH is around 1-2 and the low pH ________ the inactive form of pepsinogen and the pepsin can now act on the ________ and digest them as they come into the stomach. Once the stomach contents enter the duodenum, and the pH gets neutralized by the bicarbonate coming from the bile and pancreatic duct, pepsin then loses its _______ b/c pepsin is known as an Acid Protease- an enzyme that is optimally active at an acidic pH- when the pH becomes neutral it loses it's activity. Therefore the role of dietary pepsin in dietary protein digestion is not that great. Now you can have a patient in which the entire stomach is removed- gastrectomy- it will not affect dietary _________ digestion b/c the role of pepsin is very minimal- so losing the stomach will not produce a large change in protein digestion, but we do produce pepsin- and the pepsin is important for something else, therefore the protein digestion is not affected by the complete removal of the stomach. -The _________ secretion contains the enzymes and they are the most important ones in the dietary protein digestion. With same rational , the pancreatic acinar cells cannot produce the enzymes in the active form- if they did they would start chewing up ________cell protein and causing damage. Therefore all of the proteolytic enzymes coming from pancreatic secretion are present as an inactive precursor, known as: -___________ -_________ -____ -_________ ___ - ________ __ -These are inactive precusors produced by the _______ cells of the pancreas, released through the pancreatic duct, enters the duodenum, and there it digests the protein. These enzymes are active at a ________ pH. Therefore bicarb has to neutralize the stomach contents first and then only these enzymes can function. The pancreatic enzymes- since they are secreted in inactive form- need a way to activate them: -Trypsinogen --> trypsin: mediated by enzyme _________ (aka enterokinase)- hydrolyzes trypsinogen and makes it active. It is not present in pancreatic secretion- It is an enzyme bound to the Brush Border membrane of the ___________- the absorptive cells of the small intestine- this enzyme is membrane bound enzyme here- it cleaves the trypsinogen and activates it into trypsin, but once trypsin is formed _______ will convert chymotrypsinogen into chymotrypsin, proelastase into elastase, procarboxypeptidases into carboxypeptidase, and therefore all of the activation of the processes occurs in the small intestinal ________, and then what are the end products of the protein digestion products? When the dietary proteins are digested by pepsin, as well as T, CT, E or CP then you get a mixture of amino acids and the _____ _____. That is what he told us- the protein digestion does not go to completion in the small intestine ________ of the cell. What does that mean- look at end product: free amino acids + small peptides- the small peptides still contain a peptide bond and they have not gone to completion of digestion- primarily made up of ________ and _________ (2 and 3 Amino Acids)- the primary peptide forms you see in the small intestine after digestion. And therefore, since the digestion is not complete, you need one more step, known as ____________ digestion. and in the intracellular digestion, the small peptides will also be broken down to produce the free amino acids, and now the digestion of the protein is complete and therefore the protein digestion is not produced in the lumen outside of the enterocyte it has to go through the intracellular digestion in order to produce the free amino acids. And therefore these are the different things associated with the protein digestion in the lumen.

B2 flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Milk, egg

RIBOFLAVIN Also known as vitamin _____. Structurally has an isoalloxazine ring with ribitol side chain. The two biologically active forms of riboflavin are ________ and __________ Function: Flavins are cofactors for about 50 enzymes in mammals. They are tightly bound, sometimes covalently, to flavoproteins. Both FMN and FAD are capable of reversibly accepting two hydrogen atoms and hence are involved in a variety of oxidation-reduction reactions. Deficiency: Deficiency of riboflavin alone is rare. Deficiency symptoms include dermatitis, cheilosis and glossitis. Source: ____ _____, liver and green leafy vegetables. RDA is 1.7 mg/day.

steroid/thyroid mucus blindness xerophthalmia Hyperkeratinization infections

Retinoic acid- Action similar to ______/_______hormones, mediates most of the biological actions of vitamin A. Has a role in the regulation of certain genes involved in growth and differentiation and contributes to differentiation and maintenance of _______-secreting cells. Hormonal effect- mediated through retinoic acid receptor, which is a transcription factor that binds retinoic acid, and then translocates into nucleus to elicit its biological function. Deficiency in Vitamin A: -Night _________(nyctalopia) is one of the earliest symptoms; most important preventable cause of blindness. - Prolonged deficiency leads to blindness and ____________, pathologic dryness of the conjunctiva and cornea. - _____________ of the skin. - Reduced ability to fight __________.

FAD FMN

Riboflavin- just remember necessary for two cofactors: --______ --______ thats allh`

acid maltotriose sucrose limit dextrinase debranching maltose and maltotriose maltose, maltotriose, and ‐limit dextrins

Salivary amylase • Deactivated by ______ pH so that it remains active in the stomach only as long as it is protected from stomach acid. • If trapped within a large bolus of food inside the stomach, salivary ‐amylase can continue to digest complex carbohydrates until the bolus is broken up and exposed to stomach acid. • Thus, up to 30 - 40% of the digestion of complex carbohydrates can take place before the food reaches the small intestine. Adv Physiol Educ 34: 44-53, 2010 • Glycogen is the polysaccharide storage molecule found in animal cells and is similar in structure to amylopectin except for a greater number of branch points in glycogen. Adv Physiol Educ 34: 44-53, 2010 Sucrase‐isomaltase complex • Has two functional sites: one for ___________ and one for _________. • The sucrase‐isomaltase complex, which is actually two polypeptides (isomaltase spanning the membrane with associated sucrase) (4). • Isomaltase (also known as ______ _______ or ________ enzyme) hydrolyzes ‐1,6 glycosidic bonds at the branch points in a number of limit dextrins and ‐1,4 linkages in ________ and ________(4). • Sucrase hydrolyzes ‐1,2 glycosidic linkages between glucose and fructose molecules and thus splits sucrose • Pancreatic ‐amylase • Acts mostly in the duodenum shortly after its entry through the hepatopancreatic sphincter and generates ______, _______and ______ ______ from complex carbohydrates

gastric pancreatic carbohydrate protein lipid carbs and proteins

Salivary and ______ luminal enzymes are not necesary for complete digestion -all luminal digestion can be accomplished by _________ enzymes --->malnutrition occurs with around 90% loss of pancreatic enzymes -normally, pancreatic enzymes are responsible for : ---50% _____ digestion ---50% ______ ---90% ______ -All membrane digestion occurs in small intestine. THis type of digestion participates in digestion of ______ and ________ (not fat) along with luminal digesttion.

stem enterocyte three to five protein and nutrients 25 proliferative diarrhea 3-5

Structure of the Small Intestine: -Villi and Crypts - these structures are lined by cells. -> the cells present at the bottom in the crypts are the ______ cells, because they give rise to other cell types present in the villus. - villus lined by a single layer of epithelial cells- these cells can be enterocytes= fully differentiated intestinal cell, it can be goblet cells which secrete mucin, or endocrine cells which secrete GI hormones; But all of these cells originate from the stem cell, and then differentiate into fully differentiated absorptive __________ or goblet cell or the endocrine cell- same thing happens on other side also, and therefore when the cells actually proliferate then what happens the cells move in the upward direction from the crypts of the villi on both sides, so the cells now divide, differentiate, proliferate, and move up the column of the villus. If the cells come from both sides and join at the tip of the villus- and all of these cells are sloughed off- because there is not other place to go, they undergo apoptosis and are sloughed off. That is a very important factor: b/c entire layer of intestinal cell is renewed in your small intestine every _____ to _____ days (like removing entire carpet and putting down entirely new carpet) - what happens to the sloughed cells that contain ______ and ________- your intestine uses them, digests them and makes use of them. In fact the amount of protein that you digest in your intestine, almost ____% comes from this sloughed cells of the intestine, and therefore I tell if some of you are very proud I am a vegetarian I don't believe you because 25% of your protein is the animal protein that comes from these sloughed cells- the total daily intake of protein is only about 100g - out of that 25g comes from sloughed cells b/c it's a very highly _________ cell- why is someone is undergoing chemotherapy, something which targets your fast proliferating cells, and the intestinal cells are not cancer cells, but they are fast proliferating. And the chemotherapy agents which are supposed to target the cancer cells cannot differentiate b/t highly proliferative cancer cells and highly proliferating normal intestinal cells - therefore, the chemo agents actually affect the proliferative effect of the intestine and they cause ________ and all kinds of intestinal problems - because these are normal cells but they proliferate so fast based off the physiological need in the intestine - plays a very important role to know that the cells are replenished every ____-___days*** very important

protein

The Na+-K+-ATPase is a transport _________ as well as an ATPase. The energy released in ATP hydrolysis is used to energize the transport.

starch sucrose polysaccharide disaccharides

The average daily intake of carbohydrates is 350-400 gm (________, 60%; ________, 30% and lactose, 10%). Starch is a ____________ whereas sucrose and lactose are ____________.

blood active

The basal-lateral membrane possesses a different set of amino acid transport systems. These systems may participate in the delivery of amino acids from the mucosal cell into the _______ or under certain conditions (starvation, for example) in the transport of amino acids from the blood into the cell for cellular utilization. Very much like the Na+ gradient-dependent glucose transport, the Na+dependent amino acid transport is also electrogenic, _______ and is energized by an electrochemical Na+ gradient.

Amylase Starch and Glycogen Maltose and Maltotriose amylose Maltose, Maltotriose,alpha Limit Dextrin alpha 1,4 a-1,4 a-1,6 glucose disaccharide 3 endoglycossidase free

The digestion of these carbohydrates actually present in your diet. If you think about : starch, and then glycogen--> they need the enzyme __________- responsible for the digestion of the starch and the glycogen, does not participate in the digestion of sucrose, lactose or fructose. -so, Amylase is important for ______ and ______, and it can come from Pancreas or Salivary Glands. -salivary and pancreatic amylase, but you can forget about salivary amylase because it does not significantly contribute to the digestion of the starch, but the pancreatic amylase is very important for you -Pancreatic AMylase acts on starch and glycogen, and what are the end products of amylase digestion: coming from pancreatic juice and coming to jejunum, acts on starch and glycogen- what are the end products? -> if you have Amylose- the linear part of the starch contains only glucose residues in straight chain, then you get the products: _______ and __________- these are the two products of amylase action on the linear : these are the two end products of amylase action on linear structure of the starch known as __________ -> whereas if you take a branched carbohydrate like AP or glycogen, when the amylase acts on glycogen and amylopectin--> produce ________, ________ plus third product _______ _____ ______- the structures that contain the branch points (a-1,6 linkages) - that's because that enzyme amylase- that enzyme is selective for only ______ _____linkages it cannot touch the a-1,6 linkages, and so A-Limit Dextrin is made up of ______ linkages as well as _______linkages and it can come only from polysaccharides that contains branch points- amylopectin and glycogen. -These are the products of the amylase action on starch and glycogen - wants us to remember that amylase does not produce free _________*****, you will not get free glucose on the amylase action from starch and glycogen because maltose is a ______________ made of two glucose residues attached together and maltitriose is the _______ glucose residues attached together, even though these products contain a-1,4 linkage amylase cannot act on that, that's because amylase is known as an ___________ - means it will hydrolyze the bonds which are present well within the molecule. If it is present at the terminal part of the molecule the enzyme cannot act on that. Now if you look at the steps of the maltose, the disaccharide and there is a terminal bond, it is not present well within your big structure, therefore amylase cannot act on that, Now look at maltotriose you have two bonds and both are terminal and then enzyme cannot act on that. That is why the amylase cannot produce free glucose. so he want's us to remember: There is no _______ glucose production using the amylase- you get maltose, maltotriose on the a- limit dextrin.*****

chylomicrons apoproteins chylomicrons jejunum

The monoglyceride pathway accounts for about 70% of intestinal triglyceride synthesis. The resynthesized triglycerides leave the cell in the four of __________ which diffuse into lacteals. Chylomicrons are macromolecular particles containing 80-90% triglycerides, 8-10% phospholipids, 3% cholesterol esters and 2% protein. The proteins necessary for chylomicron synthesis are called ___________. The major protein is apoprotein B. Glycerol and medium chain fatty acids, since they are water soluble, are transported into blood without going through the chylomicron pathway. Fat-soluble vitamins are also absorbed into lacteals in the form of ___________. Fat absorption occurs predominantly in the ___________.

duodenum erythropoiesis ferritin transferrin

The quantity of iron in the body is maintained primarily by controlled absorption from the _________. Iron deficiency, enhanced ___________ and hypoxia increase intestinal iron absorption. Iron is stored in the mucosal cell as ferritin complex. When iron absorption is increased, no ferritin complex is formed and the iron is rapidly delivered into plasma. When iron absorption is depressed, more iron is trapped in the form of ________ complex and retained in the mucosal cell. Once Fe2+ leaves the mucosal cell,___________ in the circulating blood acts as a carrier for Fe2+ and delivers it to other tissues via transferrin receptors in the plasma membrane.

lumenal long medium medium immature colipase

There is only one phase involved in the digestion of dietary fats, namely _______ phase. There is no enzyme associated with the brush border membrane which is directly involved in the digestion of dietary fats. Triglycerides constitute the major part of dietary fat. About 90% of fatty acids in triglycerides is _____ chain fatty acids (16-18 carbons) and these may be saturated or unsaturated. About 10% is _____ chain fatty acids (6-12 carbons). Milk fat contains predominantly medium chain fatty acids. Two lipases are involved in the lumenal fat digestion, lingual lipase and pancreatic lipase. Lingual lipase It is secreted by Von Ebner's glands on the dorsal aspect of the tongue. It is different from pancreatic lipase. Its specificity is primarily towards _______ chain fatty acids and hence is important in the newborns in the digestion of milk fat. Also, pancreatic function is _______ in the newborns and hence lingual lipase assumes more importance. Optimal pH is around 4 and Triglyceride therefore the enzyme continues to be active even in the stomach. It does not need ______ for its activity.

beri-beri thiaminpyrophosphate (TPP)

Thiamin: -deficiency causes __________ -only 4 enzymes that require thiamine in your body: - transketolase -cytosolic enzymes - pyruvate DH - mitochondrial enzyme - a kgDH- mito -BCAKADH (branched chain alpha keto acid dehydrogenase) -mitochondiral enzyme. We also talked about Wernicke- Korsakoff syndrome so remember thiamine: ***** the cofactor form is _________ and there are four enzymes dependent on that. and then thaimine deficiency causes Beriberi wet- heart dry- CNS -this stuff you already know so read slides~re`

active glucose and fructose maltose a-dextrinase a 1,6 maltose, maltotriose mucosal

Three major enzymes - Lactase, Sucrase-isomaltase, and Glucoamylase: Lactase hydrolyzes lactose to give glucose and galactose. Sucrase-isomaltase is one polypeptide with two _______ sites. One active site possesses sucrase activity which hydrolyzes sucrose to produce _______ and _______. The same site is also responsible for the hydrolysis of ____________. Another site possesses isomaltase (aka ____________) activity, hydrolyzing______ bonds of a-limit dextrins. Glucoamylase hydrolyzes _______, _____________ and any other glucosyl oligosaccharides to produce glucose. -These monosaccharides are absorbed by the intestinal __________ cells.

bicarbonate potassium and bicarbonate acidosis hypokalemia

Transport of water and electrolytes: -small intestine absorbs sodium, potassium, and chloride, and secretes _________ - colon absorbs sodium, chloride, but secretes _____ and __________. If there is a secretory diarrhea originating from the small intestine it will lead to metabolic ___________ with no change in the plasma potassium concentration -if there is a defect in the colon that is causing secretory diarrhea it will lead to metabolic acidosis with ___________- decreased amount of potassium in the blood because they keep losing potassium in the secretion of the large intestine.

prothrombin

Treatment with antibiotics can lead to Vitamin K1 (synthesized by plants) Vitamin K2 (synthesized by vitamin K deficiency. Vitamin K deficiency can lead to deficiency of functional _________ with decreased ability of blood to clot, thus increasing the prothrombin time. Newborns are prone to vitamin K deficiency because: absorption across placenta is minimal and therefore they are born with low stores of the vitamin; breast milk is low in vitamin K; newborns are devoid of intestinal microflora. Vitamin K deficiency can also cause bone disorders since calcium-binding proteins such as osteocalcin are gamma-carboxyglutamate-containing proteins that bind calcium and help in bone mineralization.

plant skin liver calcidiol kidney calcitriol

Two forms: Ergocalciferol (D2) -from ______ Cholecalciferol (D3) -synthesized in _______ Vitamin D is a dietary requirement only in individuals with limited exposure to light. Absorption and transport: Absorbed in the intestine (similar to other fat-soluble vitamins) and transported in the plasma bound to a plasma protein-vitamin D-binding protein. D2 and D3 are prohormones and are not active. Undergoes two sequential hydroxylations. The first hydroxylation occurs in _______ at the 25th carbon atom to form 25-hydroxycholecalciferol (___________) - the predominant form of vitamin D in plasma. The second hydroxylation occurs in the ______, at the 1st carbon atom to form the physiologically active 1,25-dihydroxycholecalciferol (_________) catalyzed by the enzyme 1-hydroxylase.

Dicoumarol warfarin

Two naturally occurring forms of vitamin K: Phylloquinone (vitamin K1)-synthesized in plants Menaquinone (vitamin K2)-synthesized in bacteria. The two forms differ in the structure of the side chain. ____________ (a product of coumarin catabolism) and ________ (anticoagulant, rat poison) are anti-vitamin K compounds.

optic disk cirrhotic joint neurological carrots and spinach milk

Vit A Toxicity: Excessive intake produces a toxic syndrome called hypervitaminosis A: dry and pruritic skin (scaliness), alopecia, edema of the ____ ______ (papilledema), enlarged and ________ liver, bony hyperostosis and other bone disorders such as _____ pain, osteoporosis, and __________ symptoms such as headache, nausea, vomiting, ataxia and anorexia associated with intense headache due to increased intracranial pressure. Pregnant women should not ingest excessive quantities of vitamin A- potential for causing congenital malformations in fetus. Source: Dark green, orange or yellow vegetables such as _______ and ________, _____ cheese, butter, eggs and fish liver oils. RDA is 1.0 mg of retinol or equivalent.

nuclear Ca2+ calcium and phosphate distal parathyroid monocytes/macrophages

Vit D Function: Behaves like a steroid hormone, binding to a _______ receptor and regulating gene expression. Main function of vitamin D endocrine system is regulation of plasma ________ homeostasis by controlling cellular processes in intestine, kidneys and bone. Intestine: Stimulates the intestinal absorption of _______ and ________. Increased synthesis of a calcium & phosphate transporters in the brush border membrane, calbindin in the cytoplasm, and calcium ATPase and sodium-calcium exchanger in the basolateral membrane. Kidney: Stimulates calcium reabsorption in the ________ tubules. Requires the presence of _________ hormone. Parathyroid hormone and calcitriol work in concert in kidney and bone to increase plasma calcium concentration. Calcitriol also induces differentiation of hematopoietic cells to ________/__________, granulocytes and osteoclasts. There is evidence showing that vitamin D and calcium supplementation reduces an individual's risk of developing certain cancers.

antioxidant α-Tocopherol red cell

Vit E: The "tail" serves to anchor the vitamin in lipid membrane while the "head is the site of ________ action. There are four different forms of tocopherols & tocotrienols: α-, B-, y-, and S(deltA), depending on the number and position of the methyl groups. _________ is the only form of tocopherol that provides vitamin E activity in humans. Function: The primary function of vitamin E is as an antioxidant in prevention of the non-enzymic oxidation of unsaturated fatty acids in the cell membrane. Deficiency: Vitamin E deficiency is rare. Persons at risk include those with fat malabsorption syndromes and new borns with necrotizing enterocolitis. In humans, ____ ____ fragility is the major symptom, leading to hemolytic anemia. Deficiency can result in a variety of neurological symptoms such as ataxia, lack of reflexes, etc. Source: Vegetable oils such as corn, soy and peanut oil. RDA is 8-10 mg/day.

CH2OH Retinal Retinoic Acid Retinol Retinol binding protein Retinol and Retinal RAR (retinoic acid receptor) RXR- Retinal X receptor Xenobiotic Nuclear alcohol and aldehyde RPE PDE-6 GMP Phosphodiesterase 6 PDE5- phosphodiesterase5 retinoic acid receptor

Vitamin A occurs in 3 different forms: 1. the structure: the alcohol: ________ known as Retinol 2. retinol gets oxidized to the aldehyde-- call it _____ 3. when it is completely oxidized to carboxylic acid we call it ______ ______ ________ is the circulatory form, that is what travels in the blood, travels in the blood always bound to ______ _____ _____- because it's a fat soluble protein and it cannot travel freely. Retinol and Retinal have different biological function: -1st two ____ and ______ are the only function of the two forms in the vision because in the vision rods and cones get activated by light and then give a signal in the visual process. therefore in the visual process we have retinol and retinal which function in the vision and all other functions of vitamin A are related to Retinoic Acid. I want you to remember this: -If you have the alcohol form and the aldehyde form the only function is in the vision. whereas if you have retinoic acid- that is responsible for every other function of vitamin A, and this Retinoic Acid (RA) requires a receptor for it's biological function. and this receptor is known as _______- not present in the plasma membrane it is a nuclear receptor (just like estrogen receptor progesterone receptor) and therefore this RAR always combines with it's partner _______- can combine with either retinoic acid or any other __________- like drugs you can take- and some of the drugs can activate the RXR. Just remember Retinoic Acid acts through a __________ Receptor and that is responsible for all the biological functions of Vitamin A except the visual cycle. Only in the visual cycle the_______ and ________ plays a role. Here in the visual cycle we are talking about the function of the rods and cones, we have something called RPE (retinal pigment epithelium) and then a rod which is in close proximity to the RPE- the rod is actually a photoreceptor in the retina- rod is the one which transmits the light signal to the rest of the nueron and then to brain in visual cycle. and the signal pathway to the rod depends on the alcohol and aldehyde form of the vitamin A. Therefore here what hapens is you have the R in the Alcohol form present in the RPE then it gets converted into Altransretinal - the R gets converted into the ROH, then it gets converted into 11cisretinal --> then converted into 11cis aldehyde form. so the presence of the retinal - the aldehyde form is produced in the _______.- the retinal pigmented epithelium converts teh alcohol form into the aldehyde form - a particular isomer known as the 11 cis Retinal- it is an isoprene unit attached to the side chain and then an 11 carbon atom contains a double bond which can be trans or cis (and therefore it is converted into 11-cis retinal. and that goes into the rod, and in the rod the membrane contains a protein known as Rhodopsin ( protein that is nothing but opsin bound to Retinal- the aldehyde form) and when the retinal is bound to opsin we call it Rhodopsin- the signaling molecule in the membrane of the rod- this one contains 11cis retinal- aldehyde form and when the light comes in and attacks the membrane of the rod, then the 11cis retinal gets isomerized by photoisomerization, and the 11cis gets converted into all-trans-aldehyde form, the 11 cis becomes trans then it becomes all trans retinal. now the opsin can bind onl to 11cis, it is converted into all trans then what happens is this retinal is released out from the opsin, therefore the all trans retinal comes out of the opsin because it cannot bind the opsin in that form it has to be 11cis then only it can bind. Because of this conversion of the 11cis into all trans there is a change in teh conformation of rhodopsin, when the light strikes the rhodopsin it isomerizes the 11-cis the aldehyde form into the all trans form it changes the protein structure-- this process leads ot an activation of an enzyme ________ (phosphodiesterase 6) and enzyme which converts the cyclic GMP into______. - the cycle form of that structure is broken phosphodiesterase hydrolyzes your phosphoester linkage, converts the cyclic form of GMP into simple GMP and then this phosphodiesterase acts on this to convert to GMP, and because of this the cyclic GMP level goes down when the Cyclic GMP level goes down it really closes your sodium channel in the membrane and then causes hyperpolarization of the rod and then gives the signal. ********Just remember that this RETINAL plays a very important role in the visual cycle. RPE as the alcohol form converted to the aldehyde form gives it to the rod which converts the 11cyst into the ol-trans and then get converted to the alcohol (think he means aldehyde) form taken up by the RPE and the cycle goes again and again. -The important thing is the _______________- and that is actually activated in the visual cycle, and for that you need this Vitamin A in the aldehyde form . Now since the PDE-6 plays a very important role in the visual cycle now you know the relationship between chronic use of viagra and the vision loss- b/c what does viagra do? inhibits an enzyme called _________, so chronic use will block this enzyme PDE6- because this is an isoenzyme of PDE5, so viagra blocks both - therefore it will interfere with the vision loss with viagra: so just wants us to remmber the Vision requires the Aldehyde form and alcohol form every other function of the vitamin A requires the Retinoic Acid, and the RA acts through NOT rhodopsin but through the ____ ____ ____ and that requires all of the functions of that.

neurological Heme ALA synthetase MICROCYTIC ANEMIA Tuberculosis

Vitamin B6 - pyridoxal -dont worry about the structure in the slide what is the coenzyme form, what is the deficiency symptom and what is the biological function- that is all. needed for SOOO many enzymes in your body: deficiency can cause severe ___________ symptoms in your body -also needed for _______ Biosynthesis, the first enzyme in heme biosynthesis is called _____ ________ (delta amino levalunic Acid synthetase) which combines succinyl CoA with glycine to make delta amino levalonic acid, the first rate limiting enzyme in heme biosynth is pyridoxal dependent enzyme. so if you have pyridoxal deficiency--> it will cause ___________ __________- patients cannot synthesize hemoglobin and without Hb the erythrocytes are smaller another thing he wants us to remember about pyridoxal is drug-drug interaction: -If you have tuberculosis: --> treated with drug called isoniazid, the drug will combine with the pyridoxine and it will eliminate the pyridoxine from the body. Therefore if you are taking _____________ drug- you'll have pyridoxine deficiency (B6 deficiency)

scurvy' collagen bleeding

Vitamin C- a water soluble powerful antioxidant As a cofactor for oxidases, monooxygenases, dioxygenases, and hydroxylases, it is important in- - Detoxification in microsomes - Collagen synthesis (hydroxylating proline and lysine residues) - Conversion of dopamine to norepinephrine (dopamine--hydroxylase). Deficiency: Deficiency disorder is called _______ characterized by fatigue (first symptom), anemia, loose teeth, spongy and bleeding gums, swollen joints, and poor wound healing. Bone defect- mineralization is complete but failure in osteoid matrix formation due to defective ______. Vitamin D and vitamin C deficiency, both lead to bone disorders. Know how to differentiate the two based on additional symptoms. Vitamin K and vitamin C deficiency, both have ________ disorders. Know how to differentiate the two based on additional symptoms. Source: Citrus fruits, tomatoes and green vegetables. RDA is 60 mg/day.

mineralize

Vitamin D deficiency: -Rickets , osteomalacia, fragile bone because Vitamin D is necessary for calcium level in plasma ---> needed for bone mineralization, without ca you cannot ___________ bone--> leads to issues. might even see patietn not exposed to enough sunlight. and therefore sunlight is needed for the cholecalciferol in our body, and therefore if you are not exposed to enough sunlight you are at risk for vitamin D deficiency leading to reduced amount of calcium.

HORMONE prohormones

Vitamin D- always think about calcium -b/c it regulates calcium homeostasis- present in two different forms: 1. Ergocalciferol - present in the diet 2. Cholecalciferol - we make under the skin in response to sunlight, therefore the sunlight promotes the conversion of cholesterol into the cholecalciferol, whereas the ergocalciferol is something that we take in the diet. the important thing: VITAMIN D FUNCTIONS AS A _____________!!!!0 both D2 and D3 are called __________ because they are not biologically active- therefore they have to be converted into something called 1, 25- dihydroxy Vitamin D (calcitriol) and therefore these prohormones have to be activated first by hydroxylating at two different positions, C1 and carbon atom 25.

Nuclear

Vitamin D: -If it is hydroxylated first at the 25, which occurs in the liver, so the first hydroxylation is on carbon atom 25- liver is responsible for that. 25 Hydroxylase is an enzyme present only in the liver, therefore it converts that 25hydroxycalciferol. Now this one is sometimes called calcidiol-that's because it is a hormone which can regulate calcium homeostasis and it contains two hydroxyl groups. Now why is it diol- because the prohormone already contains one hydroxyl group in carbon atom 3- remember in the top one it already contains a hydroxyl group then add another hydroxyl group at the 25 carbon atom,, and we call it calcidiol, which is not functional so the liver made one step from the prohormone into another prohormone and then the 25 cacliferol goes to the kidney where it completes the second hydroxylation called the 1 hydroxylase, and the 1 hydroxylase is present in the kidney. therefore now you get your fully biologically active hormone 1-25claciferol it can be ergocalciferol or cholecalciferol, and then that's known as Calcitriol- it contains 3 hydroxyl groups, one on C1, C25 an the original one on C3 so we call it calcitriol and when you look at that the kidney is resposible for the final activation of the prohormone. So vitamine D2 and D3 is in inactive form goes to the liver and gets hydroxylated at carbon 25, but not active yet. Goes to the kidney gets hydroxylated at carbon atom 1 and now it's functional - the kidney is an endocrine organ now- b/c it's the one that converts the Vit D into the active form therefore 1,25dihydroxy cholecalciferol or ergocalciferol is the biologically active form and it does it's biological function through acting on it's receptor called vitamin D receptor - which is also a ________ Receptor (just like RA receptor) also acts through nuclear receptor (utDR) and for that you need 1,25 dihydroxycalciferol. That is the one that is biologically active and you need both the liver and the kidney for the activation of Vitamin D.

antioxidant

Vitamin E is a potent ________ ****, and we don't need to know anything beyond that!

carboxylation Vitamin K dependent carboxylase glutamate protein free gamma carboxy calcium binding clotting Prothrombane gammacarboxy HEMORRHAGE blood thinners

Vitamin K: another essential vitamin -all you ahve to remember is that Vitamin K is needed for one particular type of __________ reaction. -carboxylation add a carboxylatase group to your precursor substrate. you have so many carboxylases in your body, all of the carboxylases in your body depend on Biotin as the cofactor, except for 1 carboxylase- known as ____ ____ ____ _____ enzyme - only 1!!! for every other carboxylase biotin is the cofactor. what is the role of the VitK dep carboxylase- adds a carboxylate group to _________, converted into gamma carboxy glutamate. Remember the glutamate must be present in the _______, otherwise the ______ glutamate is not a substrate for vitamin K dependent carboxylase- remember that******* glutamate has to be part of the protein!! if you give free glutamate you're not converted into ______ ______ glutamate with vitamin K, it has to be a protein - dependent. There fore the same the protein dependent gamma carboxyglutamate is made and that's because this protein contains glutamate and glutamate contains a carboxylate group in the side chain b/c glutamate is an anionic amino acid, it contains two carboxylate groups, one is present in the peptide bond in teh protein, the other is in the side chain with a free negative charge, and that glutamate now contains an extra carboxylate group to the gamma carbon atom of the glutamate. Therefore it's called gamma carboxylase- this process requires Vitamin K and tehrefore the Vit K converts the glutamate in the substrate protein to gamma carboxy glutamate, now you look at what could be the biological consequence. If you have only one negative charge- it cannot bind calcium because calcium has a 2 positive charge and it cannot bind to glutamate with a one negative charge. but it it's converted into gammacarboxyglutamate, now calcium can interact with the two negative charges and therefore we are now talking about the protein which has the biological function to bind calcium, and only those proteins are substrates for vitamin K dependent carboxylation. Because the purpose of the Vitamin K dependent carboxylation is to convert the protein into a _______ ______ protein, and the function is required in ________ because Ca plays a very important role in clotting. ad the proteins which are substrates for vitamin K dependent carboxylase is known as __________- known as factor 2, 7, 9, 10- these are the four important proteins in the clotting cascade which all require bound calcium. Butt they cannot bind calcium unless some of the lutamate is converted into ______________ glutamate,and because they have to bind calcium through the clotting function they depend upon vitamin K for their function. without vit K prothrombane cannot be activted because it cannot bind calcium and therefore if you have vitamin K deficiency- you'll have a defective clotting process- because you cannot have prothrombane to bind calcium or factors 7,9, and 10 to bind calcium so you cannot have clotting and this increases risk for __________. this is very important that Vitamin K: -interferes with clotting -increases the clinical parameter known as Prothrombane Time - remember Factor 2 another name is prothrombin, and prothrombin is one of the substrates for Vitamin K carboxylation ,and therefore there is a clinical test that they look at your ability to clot in your blood- PT- a specific value (a few seconds etc) but in Vit K deficiency your prothrombane cannot bind clacium because there are reduced amounts of gammcarboxy glutamate and therefore time needed for prothrombane from the patient to cause clotting is extended and therefore the prothrombane time goes up above the normal level which is the diagnosis for Vitamin K deficiency. *********He wants us to remember Vitamin K and that Vitamin K dependent Carboxylase is inhibited by the so called ______ ______ : cumadine, warfarin, dicumarol - all drugs used for patients to prevent clotting (give to patients post heart surgery) -they are very important inhibitors of Vitamin K dependent carboxylase, therefore you have to know what is the role of this warfarin and the other things so this is the reaction in which glutamate that is present in the protein gets gammacarboxylated and you need vitamin K and the vit K is inhibited by warfarin, dicumarol, etc. and therefore the function- how these blood thinners work- because they interfere with the biological function of vitamin K in converting the glutamate in target protein into the functionally calcium binding protein.

chylomicrons liver

Vitamins: water soluble and lipid soluble Lipid soluble: AEDK- where do they end up after absorption? in _________! because all fat soluble vitamins are assembled in chylomicrons, they go through the thoracic duct into the systemic circulation. Every other water soluble vitamin are abosrbed into the portal blood and then go into the _______*** remember absorption route difference.

B5 coenzyme A eggs, liver

you can read about panthothenate: patothenate remember is needed for Conenzyme A- the coenzyme form PANTOTHENIC ACID Also called vitamin ______. Has a B-alanine and a pantoic acid residue attached together. Functions: The vitamin has two functions: in the biosynthesis of ________ _____and in the biosynthesis of 4'- phosphopantetheine, the prosthetic group of the enzyme fatty acid synthase. Coenzyme A is used in a variety of reactions like Krebs cycle, fatty acid synthesis and degradation, amino acid metabolism, ketone body metabolism and cholesterol synthesis. In these reactions, it is involved in the activation of carboxyl groups and acyl group transfers forming a thio-ester linkage. Deficiency: No deficiency disorder has been characterized in humans. Source: Widely distributed, _____, ______ and yeast are the most important. No RDA has been established.

lipase lipase bile salts colipase triglyceride

•Bile salts promote micelle formation but inhibit _____ activity. •Colipase anchors ________ to fat droplet‐water interface preventing displacement of lipase by bile salts. •In other words, colipase prevents the inhibitory effect of _____ ______ on lipase activity. •Colipase deficiency can present as a pediatric malabsorption syndrome with chronic diarrhea, abdominal distention, and failure to thrive. •Pancreatic lipase •Secreted in its active form, pancreatic ________ is needed to facilitate digestion. •Pancreatic co‐ lipase is secreted as procolipase and is activated by trypsin. •Colipase likely binds to the dietary fat and to lipase to allow the _________ to enter the active site of the lipase enzyme to be hydrolyzed (10).

protease Gastric acid Endopeptidases Exopeptidases Carboxypeptidase

•Proteins or polypeptides •Begin to be broken down in the stomach under the action of the _______ pepsin (4). •Pepsin is secreted by chief cells in the gastric mucosa as pepsinogen, a larger inactive form of the enzyme, also known as a zymogen. •_____ ______ (HCl, secreted by the parietal cells) alters the conformation of pepsinogen so that it can cleave itself and become active pepsin in the stomach. •_____ hydrolyze interior peptide bonds of proteins. •_________ hydrolyze terminal AAs. •Aminopeptidase, an enzyme in the brush border of the small intestine, will cleave a single amino acid from the amino terminal. •_____________, which is a digestive enzyme present in pancreatic juice, will cleave a single amino acid from the carboxylic end of the peptide. •Consumed proteins or polypeptides

luminal exopeptidases amino acids

•Proteins or polypeptides •Trypsin is the "trigger" enzyme. •Absence of trypsin alone makes it appear as if all of the pancreatic enzymes are missing. •Enterokinase is also called enteropeptidase. •All but enterokinase are ________ enzymes. •Carboxypeptidases and aminopeptidases are ___________. •Inside the cells of the mucosa, dipeptidase enzymes catalyse the breakdown of dipeptides into amino acids. •The two major pancreatic proteases are trypsin and chymotrypsin. •They cannot digest proteins and peptides to single______ ________. •Secretory vesicles contain a trypsin inhibitor which serves as a safeguard should pancreatic trypsinogen be activated to trypsin; following exocytosis this inhibitor is diluted out and becomes ineffective.