Rao Digestion and Absorpton

What kind of regulation is there for glucose absorption?

With these transporters, intestine has a high capacity to absorb glucose, and there is only a little regulation in sugar transport process in the intestine. Predominantly rate of transport decided by the concentration of glucose.

How much fluid is handled by the GI tract? Is fluid important in the GI tract?

a total of 9L fluid is handled by the GI tract daily (much of that comes from secretions in the body) The primary function of GI tract is digestion and absorption of nutrients, which needs a fluid environment.

Na+ is absorbed from the lumen of colon by 2 different mechanisms

a) aldosterone-sensitive electrogenic Na+ channels, b) Na+ H+ exchanger (NHE). In the basolateral membrane NKA pumps Na+ out to interstitial space

Na+ is absorbed from the lumen of small intestine by 4 different mechanisms

a) restricted diffusion Na+ channels, b) co-transport with organic solutes such as glucose and amino acids, c) Na+ -Cl- cotransporter and d) Na+ H+ exchanger (NHE).

How does abetalipoproteinemia cause steatorrhea ?

abetalipoproteinemia is characterized by inadequate chylomicron formation. This is caused by *failure to synthesize MTP* which is necessary for initial steps that bring Apo-B together with triglyceride during chylomicron formation.

What do experiments show about the presence or absence of oxygen for glucose transport

in the absence of oxygen and diminished energy production in the cell, glucose is absorbed by simple diffusion. On the other hand, in the presence of oxygen and active energy production, glucose absorption is greater, but high glucose concentration the transport mechanism is saturated, suggesting that there an energy-dependent, carrier-mediated active transport process is involved

Where does protein digestion begin?

in the stomach with pepsin

What are the major types of glucose transporters in humans

major types of glucose transporters, SGLT1, GLUT5 and GLUT2

As the lipid digestion products are insoluble, ________ is the important step in the absorption of lipids.

micelle formation they help diffusion through unstirred aqueous layer and therefore increase the concentration for absorption.

Predominate mechanism of vitamin absorption Which vitamin (their characteristics, not specific ones) are poorly permeable

passive diffusion Highly ionized and high molecular weight vitamins are poorly permeable.

natural protection from pancreatitis

separation of zymogens and lysosomes; inactivation by trypsin or auto digestion; trypsin inhibitors

All fat digestion products are absorbed by __________ - evidence suggests that __________ transport process exists.

simple diffusion; carrier protein-dependent transport

In the proximal intestine transport occurs mainly through _________, where in the ileum __________ is prominent.

solute contransporter and NHE; Na+ -Cl cotransporter

Which vitamins are actively transported? Where does this occur predominately?

thiamine, vitamin C, folate and B12 Transport occurs predominantly in upper small intestine, except that B12 transport occurs in the ileum and requires intrinsic factor.

Pepsinogen - what activates it - what kind of enzyme - optimum pH - what kind of bonds does it cleave

- acid activate pepsinogen to pepin - endopeptidase - optimum pH 1-3; inactivated in duodenum at pH > 4.5 - cleaves bonds with aromatic AA like Phe

Water absorption in intestine always occurs in response to osmotic pressure created by transport of solutes and ions. What is the 3 compartment model

Absorption of solutes from the intestinal lumen (*first compartment*) creates a local osmotic gradient causing the water to move across the epithelium into interstitial space (*second compartment*). As the water fills the interstitial space the hydrostatic pressure increases that forces water across the basement membrane and across the capillary wall. Capillary filling is in balance with the lymphatics.

Iron absorption occurs predominately in the

Absorption predominantly occurs in the proximal intestine

some external autonomic regulation occurs mainly in the colon. What increases/ decreases absorption?

Adrenergic and anticholinergic stimulus increases NaCl absorption, and cholinergic and anti-adrenergic stimuli inhibit absorption

_______ released from NPY center is an antagonist of MC4R and blocks POMC response.

AgRP

What issue of motility can lead to steatorrhea ?

Although there are no disease associated with it, any factor that *accelerate gastric emptying* and/or intestinal transit may result in steatorrhea.

Amylases break what bond? What are the products?

Amylases break only ⍺1-4 into diasaccharides, and therefore the products are maltose and limit dextrins (from amylopectin with the branch point ⍺1-6 bonds). EXHAUSTIVE DIGESTION BY AMYLASE DOES NOT PRODUCE GLUCOSE Luminal digestion by amylases produce limit dextrins, maltotriose and maltose.

On the apical side, how does calcium get in? What happens to calcium once in the cytosol? Why is this important this happens? How does it exit? With or against the gradient?

Apical Ca2+ channels, such as *TRPV6* in the cytosol it binds to Ca2+ binding protein, *Calbindin*. This is important to *avoid change in intracellular concentration of free Ca2+* and change in cell functions. Exit of Ca2+ at the basolateral membrane occurs *against the electrochemical gradient* by a *Ca2+ ATPase*.

What diseases can cause steatorrhea due to a defect in pancreatic enzyme secretions?

CF, Chronic Pancreatitis Zollinger Ellison Syndrome may reduce the pH of duodenal contents and the pancreatic lipases may get inactivated - triglyceride appears in the stool.

FOOD INTAKE IS REGULATED BY SIGNALS FROM THE __________ SYSTEMS NTS: _______

ENDOCRINE, NERVOUS AND GI Nucleus tractus solitarius

What are the pancreatic endoproteases?

Endoproteases are trypsinogen and chymotrypsinogen

Fat soluble vitamins require what for absorption?

Fat soluble vitamins (A, D, E, K) requires to form *micelles* for absorption and incorporated into *chylomicrons*. Diseases with fat malabsorption may lead to deficiency of these vitamins.

Two pathways integrate in this center b) the second that stimulate food intake and inhibit metabolism.

Hunger --> NPY and activation Y1 --> increased food intake Satiety inhbits NPY

Protein Malabsorption - what is defective in Hartnups Do those amino acids ever appear in the blood? Why?

In HARTNUPS DISEASE, the NEUTRAL AMINO ACID CARRIER that actively transport neutral amino acid is deficient neutral amino acids appear in blood due to dipeptide transport

Protein Malabsorption - what is defective in cystinuria

In cystinuric patients the transport of free Arg is defective. the basic amino acid transporter Y+ is defective or missing. (transported fine if dipeptide) Cystine is known to be transported by this transporter as well.

What are the differences in the movement of water in the duodenum and ileum ?

In duodenum when the hyperosmotic chyme from stomach enters duodenum the fluid from second compartment moves into the lumen to maintain isotonicity. In the ileum due to solute absorption the fluid moves from the lumen to second compartment, resulting in net absorption of water.

How does PTH increase calcium absorption?

Parathyroid hormone, PTH, *indirectly* regulates intestinal Ca2+ absorption by *regulating V1.25 (OH)2-D3 production in kidney*.

In the saliva, digetion in the stomach in the small intestine

Saliva- lingual lipase, alpha amylase Stomach - protein digestion by pepsin small intestine - pancreatic enzymes such proteases, amylase, lipase and nucleases as well by disaccharidases and peptidases in the small intestine.

some external autonomic regulation occurs mainly in the colon. What increases / decreases secretion

Serotonin, dopamine, enkephalin have secretory response, and Morphine, codeine inhibit secretion and increase absorption resulting in constipation.

What are the end product of membrane carb digestion

So the end products are glucose, fructose and galactose.

What layers do nutrient have to go through in order to get to the walls of capillaries and lymphatics

So, the absorptive pathway consists of the unstirred layer of mucus, the *glycocalyx*, the cell membrane, the cytoplasm, the basolateral membrane, the intercellular space, the basement membrane, and the walls of capillaries and lymphatics.

________ is the presence of excessive fat in the stool. Less than ____ g fatty acid in the stool per day is normal. Any thing higher than that suggests _______.

Steatorrhea; 7; malabsorption

IRON ABSORPTION IS REGULALATED BY LEVELS OF __________ How significant is iron absorption

TRANFERRIN (TF) Iron absorption under normal condition is minimal as the body iron is conserved.

Assimilation of carbohydrate - what is the rate limiting step? What part of the tract is mainly responsible ?

The capacity of carbohydrate digestion is very high. The rate limiting step is absorption, not the digestion. Carbohydrate digestion is predominantly completed by the proximal jejunum.

Electrolyte and fluid secretion occurs in the ______ of small intestine and colon.

crypts

Fe2+may bind to ______ for storage or transported across the basolateral membrane by a pump named _________

ferritin; ferroprotein 1 or FPN1.

Some of the digestive enzymes are located in the luminal membrane of epithelial cells, which is referred to as

"membrane digestion" (disaccharidases).

How is Fe2+ transported into the cytoplasm ? What other enzymes/transporters are necessary?

*Divalent metal ion transporter (DMT1)* transports Fe2+ iron into cytoplasm. This is a secondary active transport mechanism coupled to Na+H+ exchanger and Na+K+ ATPase.

In osmotic diarrhea, what changes in osmolarity occur ? What happens to the osmotic pressure? What are some causes

*accumulation of non-absorbable solutes* in the intestine, thus increasing the osmolarity in the lumen Increase in osmolarity in the lumen drives fluid movement into the lumen.

Interrupted enterohepatic circulation causing steatorrhea

*ileal resection, biliary obstruction or cholestatic liver* disease leads to *reduction of bile acids* and reduced fat absorption and steatorrhea. However, requires that greater than 80% reduction in bile acid occurs to cause steatorrhea.

Look at this graph of carb malabsorption A. NORMAL B. PATIENT WITH FAMILIAL RENAL GLUCOSURIA C. CELIAC DISEASE OR GLUTEN SESITVE ENTEROPATHY

- In patient with familial renal glucosuria the fructose absorption was normal, but glucose absorption was blunted -SGLT1 is absent and therefore prevent glucose absorption - Celiac disease however has a general defect in nutrient absorption and therefore absorption of both fructose and glucose were affected

SGLT1 is located where? binds what? After binding what happens? Is it active?

-apical membrane of enterocytes - glucose and galactose (compete w eachother) ; 2 Na+ - rotates with the binding sites facing the cytoplasm, where the sodium and glucose are released into cytoplasm. The carrier is rotated back to the apical brush border membrane. - secondary active; relies on the concentration gradient of Na that is actively created by NaK ATPase

Luminal digestion by gastric and pancreatic proteases result in the production of three types of products

1) free amino acids, 2) dipeptides and tripeptides and 3) larger peptides.

To understand the absorption of protein digestion endo products you should 3 important questions:

1. In what form protein digestion products cross BB? 2. What are the transporters involved? 3. In what form they leave epithelial cells into circulation?

Amino acids are transported by carrier mediated mechanism using following transporters:

1. Sodium-AA acid transporter - similar to SGLT1, dep on Na concentration gradient, secondary active 2. Facilitated AA transporter - one for specific groups (neutral, basic, acidic) ; ind of energy, Na 3. PAT Proteins - Proton-dep AA transporters on Apical Membrane, transport short chain AA (G,A,S,P) w/ H+ (electrogenic process)

Carbohydrates in the diet such as starch, sucrose and lactose account for ____% of calories that we assimilate.

50%

Apical membrane of crypt cells carry two types of Cl- channels.

A Ca2+ activated Cl- channel is stimulated by acetylcholine released by the ENS. The other Cl- channel is the cAMP-activated channel identical to CFTR, VIP, secretin and prostaglandin stimulate this channel by cAMP-dependent mechanism

Transcellular secretion of ______ accounts for most of the secretory activity.

Cl-

How is Chloride transported in the prox intestine and ileum? What additional is necessary in the ileum?

Cl- transport is clamped to the electrochemical gradient. In the proximal intestine, it is diffused through tight junctions, whereas it is coupled to Na+ transport in the ileum. In the basolateral membrane NKA pumps Na+ out to interstitial space

Chloride transport in the colon- what two mechanisms

Cl- transport is clamped to the electrochemical gradient. It is transported by two mechanisms: a) diffused through tight junctions, and b) Cl- HCO3-exchanger

What can cause a qualitative deficit in bile acids leading to steatorrhea

Defective conjugation or unconjugation due to bacterial overgrowth may cause fat malabsorption and steatorrhea

What form of iron is most efficienty absorbed? What in the diet can make this form? What brush border protein?

Fe2+ is absorbed more efficiently than Fe3+ Dietary ascorbic acid can convert Fe3+ to Fe2+. A brush border protein named *duodenal cytochrome B (DCYTB)* reduces ferric to ferrous iron.

How do digested nutrients get to the other side?

For assimilation of digested nutrients must traverse the epithelial barrier because the tight junctions between the epithelial cells do not allow diffusion of solutes through the intercellular space.

GLUT2 transporter - where it is and what does it transport? Energy?

GLUT2 transports fructose, glucose and galactose in the basolateral membrane. utilizes no energy- facilitated transport

GLUT5 transporter - where is it and what does it transport? Energy?

GLUT5 is on the apical membrane of enterocytes which transports fructose, and to some extent glucose - utilizes no energy - facilitated transport

SATIETY SIGNALS ARE INTEGRATED IN THE ________

HYPOTHALAMUS The most important site of food intake regulation is the arcuate nucleus in the hypothalamus. **It is impossible to saturate the digestive and absorptive capacities of GI tract

___________ on the basolateral membrane oxidizes Fe2+ to Fe3+, which then binds to ________for transport in the blood. The level of this transporter protein appears to regulated iron absorption.

Hephaestin (HEPH); transferrin

Secretory diarrhea is marked by excessive...

However, an excessive Cl- and fluid secretion is considered secretory diarrhea.

________ occurs if duodenal absorption of iron is impaired

Iron-deficiency anemia

What happens to the larger peptides? What happens to free AA?

Larger peptides are hydrolyzed by brush border peptidases to free aa and dipeptides/tripeptides Amino acids and dipeptides/tripeptides are absorbed across the brush border.

Describe what happens with membrane digestion

Limit dextrin from amylopectin is hydrolyzed by membrane-bound enzyme called *glucoamylase*. Disaccharides in the brush border membranes such as sucrase, lactase, isomaltase (⍺1-6) and trehalase (⍺1-1) *hydrolyze disaccharides into monosaccharides*. ***Sucrase-isomaltase is a compound protein.

Steatorrhea: What system is very important in fat absorption? Disease?

Lymphatic system very important for fat absorption. If there is obstruction in lymphatics fat malabsorption can occur. There are two rare conditions congenital lymphangiectasia and Whipple's disease.

Two pathways integrate in this center: a) one that inhibits food intake and increases metabolism,

Melanocortin pathway: appetite inhibiting neurons containing POMC --> releases ⍺-MSH --> binds to melanocortin receptors (MC4R) --> appetite inhibited and metabolism increased

NaCl in the lumen creates osmotic gradient, which draws water into the lumen. Describe how this occurs

N+K+2Cl- channel in the basolateral membrane transports 2 Cl- along with a Na and a K equivalents. The Na is pumped out of the cell by NKA, and therefore, and active transport process. Cl- is then transported to the lumen through an apical Cl- channel. Na diffuses through paracellular space along the electrochemical gradient.

Does digestion occur in the colon

No No digestion occurs in the colon, except for digestion caused by bacteria residing the colon

CA++ ABSORBTION DEPENDS ON ______ and _______ (hormones) What part of the GI tract?

PARATHYROID HORMONE AND VITAMIN D It is absorbed predominantly in the proximal small intestine.

What kind of gradient is required for peptide transporters? What exchanger is functionally coupled to this?

Peptide transporters are independent of Na+, but activated by inwardly directed *H+ gradient*. The *acidic microenvironment* near brush border is the driving force H+-peptide cotransporters ( such as PEPT1) -functionally coupled to Na+-H+- exchanger ( that is NHE3).

How is potassium transported in the small intestine and the colon?

Potassium is absorbed in the small intestine by diffusion through paracellular space. In colon, both apical and basolateral membranes are permeable to potassium. Thus potassium is secreted into the lumen of colon due to high concentration of potassium in the cytoplasm

What genetic anomalies are found with people in heritdary pancreatitis

Researchers have identified a patient with G to A single nucleotide mutation in trypsin gene. The result SNP is substitution of Arg117 with a His and the mutant trypsin cannot be inactivated by trypsin or auto digestion leading to pancreatitis (hereditary pancreatitis)

SGLT1 transporter - what does it transport and what energy method?

SGLT1 transports glucose and galactose by a secondary active transport mechanism.

The intestines are typically adaptive to resection and starvation...what are some exceptions

The exceptions to adaptation are vitamin *B12 absorption* from ileum, *bile acid* reabsorption from ileum, and *genetic lactase* insufficiency. These are not compensated and therefore result in pathologic conditions.

What is a mechanism of acute pancreatitis? What causes the auto-digestion of cells to occur?

The mechanism of premature activation of proteases include lysosomal hydrolases. *Trypsin* activation can lead to activation of the entire cascade of proteases. The result is auto digestion of cells

What are causes of death from diarrhea ?

The resulting hypovolemia, metabolic acidosis, hypokalemia and circulatory collapse are the causes of death.

In the intestinal lumen, describe water absorption and ionic concentrations

Therefore, the ionic concentrations in the intestinal lumen are close to those of plasma. Water is predominantly absorbed through the tight junctions along the osmotic gradient created by electrolyte absorption.

Two causes of secretory diarrhea

These pathogenic bacteria release certain enterotoxins that activate receptors on enterocytes and activate intracellular signaling (cAMP) to activate the Cl- channels Excessive production and release of secretory hormones such as VIP can cause secretory diarrhea

What transport and absorptive processes are used for nutrients to get across

Transport or absorptive processes include *pinocytosis* at the base of microvilli (proteins), *passive diffusion* (lipid soluble, ions by TJ), facilitated diffusion, and active transport.

Na + transporters - which are electroneutral and which are electrogenic

Transport through *Na+ -Cl- cotransporter and NHE* is electroneutral and therefore, dependent on concentration gradient between lumen and cytoplasm. On the other hand transport through *Na+ channels and organic solute co-transporters* is electrogenic and increase negative membrane potential across the apical membrane.

What amino acid in particular is a problem in Hartnups dx? What downstream effects?

Trp malabsorption and excretion in urine result in decrease in plasma Trp. Since Trp is the precursor for niacin synthesis, niacin deficiency (Pellagra) occurs in these patients. There is also decreased serotonin levels leading to neurologic symptoms.

Besides digesting protein you eat, what else does trypsin do?

Trypsin activates other proteases.

What enzyme activates trypsinogen? Where is it located? Specificity of action?

Trypsinogen is activated by an enzyme named *enterokinase* that is present on brush border membrane of duodenal enterocytes Enterokinase has a high specificity in action. It cleaves the N-terminal hexapeptide with the sequence of V-D-D-D-D-K. One can add this sequence to the N-terminus of any protein, and enterokinase can cleave that protein in this specific site.

Protein is further digested in the duodenum and jejunum by pancreatic proteases - what are the two types ?

Two types proteases are endoproteases and exoproteases.

How does Vit D increase calcium absorption?

Vit D binds to nuclear receptors and induce gene expression changes to increase in the levels of TRPV6, calbindin and Ca2+ ATPase.

Bile salts form mixed micelles with ___________. The conjugated bile salts have lower critical micellar concentration and more efficient in dissolving lipids.

cholesterol, FA and MG.(monoglycerides)

partial digestion of carbohydrates can lead to

diarrhea (undigested materials in colon and osmotic effects) bloating (bacteria can digest the partially digested carbohydrates and generate gas and acid) and abdominal pain.

How fast are dipeptides and tripeptides absorbed? Where are they absorbed most?

dipeptides and tripeptides could be transported, but also peptide absorption is faster than that of free amino acids The transport of peptides is greater in *proximal* intestine, whereas free aa transport is greater in the distal.

Riboflavin is absorbed by ______ diffusion, and B6 is absorbed by ______ diffusion.

facilitated; simple