Lipids, Vitamins, and Minerals: Absorption and Digestion

Recycling of Bile Acids/Salts

90-95% of the bile salts secreted by the liver are reabsorbed fro the SI and recirculated to the liver for use again (*enterohepatic circulation*) -20 grams of bile acids secreted daily with 19 grams being re-absorbed by the ileum. >Less than 1 gram excreted in feces -Most bile salts are absorbed in the terminal ileum by *secondary active co-transport with Na+* that is specific for these conjugated bile acids with taurine and glycine -Some bile salts are de-conjugated (converted back to bile acids) by colonic bacteria and then absorbed by simple diffusion due to their high lipid solubility. -Bile salts entering the liver via PORTAL VEINS are avidly taken up by hepatocytes. -IN hepatocytes: Unconjugated bile acids must be conjugated BEFORE they are secreted again.

Pancreatic Lipase

ACTIVE enzyme that is secreted by the pancreas into the duodenum in response to *CCK* -Pancreatic lipase activity optimum at pH 8 -Hydrolyzes TAG molecules to one molecules of MAG and two free FAs. -Potential problem: The action of pancreatic lipase is INACTIVATED by bile salts. -Bile salts displace pancreatic lipase at the lipid-water interface of the emulsified lipid droplets. -Solution: *Colipase*

Apoproteins

Apoproteins are synthesized by the intestinal epithelial cells -Essential for the absorption of chylomicrons -Failure to synthesize *Apo B* (Beta-lipoproteins) results in *Abetalipoproteinemia*

Calcium absorption

Calcium absorption by the SI is regulated by circulating levels of plasma calcium concentration -Lowering the calcium concentration stimulates the release of *parathyroid hormone (PTH)* which stimulates the conversion of vitamin D to its active metabolite vitamin D3 in the kidney. -Active vitamin D3 will increase the calcium entry thru the calcium channels (TRPV-6) at the luminal membrane >Also increase the synthesis of cytosolic binding proteins *Calbindin* in intestinal cells. -Calbindin binds calcium, keeping the intracellular free calcium levels low, maintaining a gradient for calcium entry into the cell, and allowing calcium-dependent messenger systems to function properly -The calcium exits the basolateral side thru *Calcium ATPase pumps* and *Na+ Ca2+ anti porters* >The activity of calcium ATPase is also increased by vitamin D.

Bile Acids

Cholesterol derivatives synthesized in the liver -Cholic acid and chenodeoxycholic acid >They can be conjugated with hydrophilic side groups: Taurine and glycine >Helps enhance their amphipathic properties and water solubility becoming BILE SALTS

Lipid digestion and absorption problem

the gut lumen is an AQUEOUS environment -Unlike salts and solutes, fats are NOT ingested in a convenient form for digestion or absorption >Most lipids are water INSOLUBLE -Absorption must occur in aqueous phase -Solution: Transform fats into water soluble molecules >Increase solubility of fats by mixing, metabolism, and detergents

Lipid Digestion in the small intestines

MAJOR contributor: Most lipid digestion occurs in the SI where conditions are more favorable than the stomach -*Bile salts* are secreted into the lumen of the small intestines -Bile salts with lysolecithin and products of lipid digestions surround and EMULSIFY dietary lipids. -Emulsification occurs -Physical events must occur to REDUCE the size of the fat droplets in the gut lumen (become very small) -Vigorous *gastric and intestinal peristalsis* shears the droplets into SMALLER sizes >These are prevented from re-aggregating with other droplets by emulsification agents -Large lipid molecules are still not easily emulsified into small particles (especially at the low pH of the stomach) and cannot easily be absorbed >MUST be digested by LIPASES.

Dietary Iron

More intake in females then males -Dietary iron is released in relatively large amounts after digestion of proteins, which are abundant in meals -Iron is absorbed primarily in the duodenum and proximal jejunum

Cylomicron Packaging

Packaged in secretory vesicles on the Golgi apparatus -The secretory vesicles migrate to the basolateral membrane and there is *exocytosis* of the chylomicrons -The chylomicrons are TOO large to enter the vascular capillaries but can enter the *lymphatic capillaries (lacteals)* by moving between the endothelial cells that line the lacteals >Unlike amino acids and monosaccharides which travel into the portal vein. -The lymphatic circulation carries the chylomicrons to the *thoracic duct* >Empties into the bloodstream

Pancreas not excreting sufficient bicarbonate

Pancreas may fail to secrete SUFFICIENT quantities of bicarbonate in pancreatic juice -Disorders of exocrine pancreas can lead to impaired bicarbonate secretion and also impaired enzyme secretions. >*Pancreatitis*

Pancreatic Enzymes (actions)

Pancreatic enzymes are secreted into the SI to accomplish the digestive work. -Most important role in infants for milk digestion: Contains abundant TGs. -In adults: Lipases act in the stomach to convert dietary TGs to MAGs and FAs.

Emulsification

Produces small droplets of lipid dispersed in the aqueous solution of the intestinal lumen -Creates a LARGE surface area for the action of pancreatic enzymes. -Emulsification agents: Dietary proteins, fatty acids, and bile salts secreted by the liver/gallbladder. >*Amphipathic* properties stabilize the water-lipid interface -Need pH >6 for stable emulsification

Bacterial overgrowth

Reduces the effectiveness of bile salts by deconjugating them -Bacterial actions remove GLYCINE and TAURINE from bile salts= converts them back to bile acids. -Bile acids are generally non-ionized form in intestinal pH. >Non ionized bile acid is lipid soluble and readily absorbed by diffusion across the intestinal epithelial cells. -Bacterial causes bile acids to be absorbed TOO EARLY before reaching the ileum BEFORE micelle formation and lipid absorption is completed. -Decreased pH in the intestinal lumen also promotes early absorption of bile acids by converting them to their non-ionized form.

Bile salts entering the colon

Remaining 5-10% of bile salts enter the colon and is converted by colonic bacteria to secondary bile salts: *deoxycholic acid lithocholic acid* -Much of the colonic deoxycholate is absorbed -Lithocholic acid is relatively insoluble and is mostly EXCRETED in the stool -Bile salts and bile acids lost in the stool are replaced by synthesis in the liver. -Bile salt pool is recycled from meals about 6-8 times a day.

Short and medium chain Fatty acids

SCFA and MCFA do NOT need to be carried in micelles to be absorbed. -Can diffuse thru intestinal epithelium and enter portal circulation. -Cholesterol is absorbed more slowly than others.

Saliva Formation

Saliva: water, electrolytes, α-amylase, lingual lipase, kallikrein, and mucus -α-amylase: begins initial digestion of carbohydrates -Lingual lipase: begins initial digestion of lipids -Mucin glycoproteins: lubrication -Kallikrein: bradykinin-> vasodilator increases blood flow during salivation

Phospholipase A2

Secreted as a proenzyme (inactive) -Activated by TRYPSIN -Hydrolyzes phospholipids (lecithins) to LYSOLECITHINS and fatty acids.

Cholesterol Ester Hydrolase

Secreted as an ACTIVE enzyme and hydrolyzes cholesterol ester to free cholesterol and free FAs. -Hydrolyzes ester linkages of triglycerides= glycerol + free FAs >Glycerol forms from hydrolysis of ESTER bonds of TAGs.

Water Soluble Vitamins

*B1, B2, B6, B16, C, biotin, folic acid, nicotinic acid, and pantothenic acid* -Absorption of water soluble vitamins occur via *Na+ dependent cotransporter* mechanism in the SI. -The small intestine epithelial cells utilize FACILITATED diffusion to promote absorption of Vitamin B2 and B6. B1: Thiamine B2: Riboflavin B3: Niacin B6: Riboflavin B9: Folic Acid B12: Cobalamin

Minerals: Divalent Cation Absorption

*Calcium and Iron* -Calcium and iron are absorbed early in the SI from the duodenum thru early to mid jejunum -The early part of SI has lower pH: Favors reduced Fe2+ and keeps the cations from forming insoluble salts.

Abetalipoproteinemia

*Failure to synthesize ApoB* -Condition in which a person is UNABLE to absorb chylomicrons and UNABLE to absorb DIETARY LIPIDS

Pancreatic Insufficiency

*Leads to diseases of exocrine pancreas: Chronic pancreatitis and Cystic Fibrosis* -Results in failure to secrete adequate amounts of pancreatic enzymes important for lipid digestion, pancreatic lipase and colipase, cholesterol ester hydrolase, Phospholipase A2. -Absence of pancreatic lipase: TAGs cannot be digested to MAG and free FAs. *Undigested TAGs are NOT absorbed and are excreted in feces*

Gastrectomy

*Partial or full surgical removal of the stomach* -Leads to loss of the source of *intrinsic factor* from parietal cells -After gastrectomy: Patients fail to absorb vitamin B12 from the ileum -Eventually become Vitamin B12 deficient >Can develop *Pernicious Anemia* -To prevent pernicious anemia: Vitamin B12 must be administered by INJECTION every few month -Orally supplemented vitamin B12 cannot be absorbed due to absence of intrinsic factor.

Ileal Restriction

*Removal of the Ileum* -Interrupts the enterohepatic circulation of bile salts -Then are excreted in feces rather than being returned to the liver -The synthesis of new bile salts cannot keep pace with the fecal loss= total bile salt pool is reduced.

Bile Salts

*Taurocholic and Glycocholic acids* -Bile salts are secreted from the liver and are concentrated in the gallbladder -Ultimately secreted into the gut lumen -Fats in the gut lumen stimulate the release of the hormone CCK >Promotes release of bile from the gallbladder -As lipids are digested the emulsified fat droplets spontaneously breakdown into micelles. -Hydrophobic centers act as a sink for the water insoluble products of lipolysis >Fatty acids, monoglycerides, cholesterol, fat-soluble vitamins.

Absorption of Vitamin B12

*Vitamin B12= Cobalamin* -Dietary Vitamin B12 is released from food by the digestive action of pepsin in the stomach -Free vitamin B12 binds to *R Proteins (Haptocorrin)* which are secreted in salivary juices -In the duodenum, pancreatic proteases degrade the R proteins causing vitamin B12 to be transferred to *Intrinsic Factor* >IF= Glycoprotein secreted from gastric parietal cells. -Vitamin B12-IF complex is resistant to the degradative actions of pancreatic proteases and travel to the ileum where there is a specific transport mechanism involving *vitamin B12* complexing with *Transcobalamin II* for its absorption. -Transcobalamin II binds vitamin B12 intracellularly in ileal epithelium >Transcellular transit across epithelium

Fat soluble Vitamins

*Vitamins A,D,E,K* -Absorbed as the same manner as dietary lipids -In the intestinal lumen, fat soluble vitamins are incorporated into MICELLES and transported to the apical membrane of the intestinal cells -Diffuse across the apical membrane into the cells and incorporated in *chylomicrons* and then extruded into lymph >Delivered to general circulation

Bile Composition

-Bile salts -Cholesterol -Phospholipids -Bile Pigments -Ions -Water

Calcium Roles

-Bone and tooth formation -Cofactors for enzymes and proteins -Blood clotting -Muscle contraction -Nerve transmission -Intracellular signalling for hormone action.

Iron (Roles in the body)

-Hemoglobin: Oxygen transport and storage >Majority of stores in RBCs -Energy metabolism: Cytochromes are heme proteins -Immune system: Oxidant production and detoxification -DNA synthesis require iron bound proteins

Chewing

-Mixes food with saliva: lubricating for swallowing -Reduces food particle size -Mixes ingested carbohydrates with *salivary amylase* to begin digestion -Mixes ingested fats with *lingual lipase* to begin digestion *Voluntary*

Final products of lipid digestion

-Monoglycerides (MAGs) -Fatty acids (FAs) -Cholesterol -Lysolecithin -Glycerol: can transfer freely across the membrane -All are hydrophobic except glycerol >Most are not water soluble -Hydrophobic digestive products must be solublized in *micelles* and transported to move lipids to the apical membrane of intestinal cells for absorption. >Micelles function to move lipids thru the unstirred water layer, allowing lipids to access the enterocytes. >Help with carrying MAGs, FAs, cholesterol, and fat-soluble vitamins.

Pancreatic Enzymes (list)

-Pancreatic Lipase -Cholesterol Ester Hydrolase -Phospholipase A2 -Colipase: Special protein

Absorbable lipids

-TAGs break down with pancreatic lipase-> form 2-MAG and Fatty acids which are absorbable -Lecithin (phosphatidylcholine) + Phospholipase A2-> Fatty acid + Lysolecithin -Cholesterol ester + cholesterol esterase-> Cholesterol + Fatty acid

Chylomicrons

Composed of TAGs and cholesterol at the core and phospholipids and apoproteins on the outside -Phospholipids cover 80% of the outside of the chylomicron surface, and the remaining 20% of the surface is covered with *apoproteins*

Gastric Secretion

Contains 4 major components -HCl and Pepsinogen: Initiates protein digestion in body and fundus of the stomach -Intrinsic factor: Required for vitamin B12 absorption in ileum >Only ESSENTIAL component of gastric juice (body and fundus) -Mucus: Protects gastric mucosa from corrosive action of HCl and lubricates gastric contents >ALL regions of the stomach -Antrum secretes gastrin and somatostatin -Fasting state: Peristalsis -Receptive relaxation when meal enters stomach >Antral systole grinds food and mixes food (NON propulsive mixing)

Deficiency of bile salts

Deficiency of bile salts interferes with the ability to for MICELLES which are necessary for solubilization of the products of lipid digestion. -Ileal restriction leads to problems for bile salts

Abnormalities of lipid digestion and absorption

Each step of lipid digestion and absorption is ESSENTIAL and if there is an issue with one can lead to problems -Pancreatic enzyme secretion -Bile salt secretion -Emulsification -Micelle formation -Diffusion of lipids into the cells -Chylomicron formation -Transfer of chylomicrons into lymph *An abnormality at ANY of these steps will interfere with lipid absorption and result in STEATORRHEA: Fat excreted into feces*

Failure to synthesize apoproteins

Failure to synthesize Apo B (Beta-lipoproteins) causes *abetalipoproteinemia* -Chylomicrons either do not form or are unable to be transported out to the intestinal cells into the lymph -Decreased absorption of lipids into blood and a buildup of lipid within the intestinal cells.

Lipid

Fats supply about 40% of calories in Western diet -9 kcal/gram of lipid -Majority of lipids are *Triglycerides (TAGs)* -Remainder of lipids are cholesterol, cholesterol ester, sterols, and phospholipids -Non-dietary lipids are made in body such as phospholipids and sterols (make bile salts, etc)

Excessive H+ secretion

Gastric parietal cells may be secreting excessive quantities of H+ causing an overload to the duodenum. -*Zollinger-Ellison Syndrome*: Tumor secretes large quantities of GASTRIN. >Elevates the levels of gastrin stimulate excessive secretion of H+ by the gastric parietal cells >The excessive H+ is delivered to the duodenum overwhelming the ability of pancreatic juices to neutralize it. >Inactivates pancreatic enzymes

Acidity of duodenal contents

If the acidic chyme delivered to the duodenum is NOT adequately neutralized by the bicarbonate containing pancreatic secretions, then pancreatic enzymes are INACTIVATED >Optimum pH for pancreatic lipase is 6 -The gastric chyme is delivered to duodenum has a pH ranging from 2 in pylorus to 4 at duodenal bulb. -Sufficient bicarbonate must be secreted in pancreatic juice to neutralize the H+ and increase the pH to the range where pancreatic enzymes function optimally. *2 possible reasons: Parietal cells excreting excessive H+ OR pancreas fails to excrete proper amount of bicarbonate*

Decreased intestinal cells for absorption

In conditions of *Tropical Sprue* the number of intestinal epithelial cells are reduced as a result of damage to the gastric mucosa which reduces the microvillar surface area. -Since lipid absorption across the apical membrane occurs by diffusion, which depends on surface area, lipid absorption is impaired due to the decrease of surface area for absorption. -Reducing microvillar surface area

Lipid Absorption (inside the cell)

Inside the intestinal epithelial cells, the products of lipid digestion are *re-esterfied* with free fatty acids on the smooth endoplasmic reticulum to form the ORIGINAL ingested lipids: TAGs, Cholesterol ester, and Phospholipid -Inside the cells, the re-esterfied lipids are packaged with *apoproteins* in lipid carrying particles called *chylomicrons*

Iron Absorption

Iron is absorbed across the apical membrane of intestinal epithelial cells: duodenum and proximal jejunum >As FREE iron (Fe2+) or as *heme iron* >Heme iron= iron bound to hemoglobin or myoglobin *Ferric salts (Fe3+)* are not soluble at pH 7 whereas *Ferrous salts (Fe2+)* are soluble. -Iron is transported across the apical membrane by ACTIVE process via carriers like the *divalent metal transporter* which is expressed abundantly in the duodenum. -Once inside the intestinal cells, heme iron is digested by lysosomal enzymes, releasing free iron. -Free iron then binds to *apoferritin* and is transported across the basolateral membrane into the blood -In the circulation: iron is bound to a beta-globulin called *transferrin* which transports it from the SI to storage sites in the liver. -From the liver: iron is transported to the bone marrow, where it is released and utilized in the synthesis of hemoglobin.

Colipase

Secreted in pancreatic juices in an INACTIVE form: *Procolipase* -Activated in the intestinal lumen by Trypsin -Colipase displaces bile salts at the lipid-water interface and binds to pancreatic lipase -With the inhibitory bile salts displaced, pancreatic lipase can proceed with its digestive functions.

Calcium

The amount of calcium entering GI is approximately half from diet. -Most dietary calcium is derived from meat and dairy products -Of calcium presented to GI tract, about 40% is absorbed.

Digestion of Lipids

The digestion of dietary lipids begins in the stomach with the action of *lingual and gastric lipases* -Digestion is completed in the small intestines with the action of pancreatic enzymes: *Pancreatic lipase, cholesterol ester hydrolase, Phospholipase A2*

Lipid digestion in the stomach

The function of the stomach in lipid digestion is the CHURN and MIX dietary lipids and to initiate enzymatic digestion -The churning action breaks the lipids into small droplets, increasing the surface area for digestive enzymes -In the stomach, the lipid droplets are emulsified (kept apart) by dietary proteins. >Bile salts are emulsifying agents but NOT present in stomach, but later in the SI. -*Lingual and gastric lipases*: Initiate lipid digestion by hydrolyzing approximately 10% (minor) of ingested triglycerides to monoglyceride (MAG) and free fatty acids (FAs). -Important contribution of stomach is the overall lipid digestion and absorption is that it empties chyme SLOWLY into the small intestine >Allows for adequate time for pancreatic enzymes to digest lipids. -The rate of *gastric emptying* which is so critically for subsequent intestinal digestive and absorptive steps is SLOWED by CCK. >CCK is secreted when dietary lipids FIRST appear in the small intestines.

Lipid Absorption

The micelles diffuse to the apical (brush-border) membrane of the intestinal epithelial cells -At the apical membrane: The lipids are released from the micelles and diffuse down their concentration gradients into the cell -The micelles do NOT enter the cell >Bile salts are left behind in the intestinal lumen to be absorbed downstream in the ILEUM -Most ingested lipids are absorbed by the duodenum to mid-jejunum: The work of the bile salts is completed LONG before they are returned to the liver via enterohepatic circulation.

Vitamin D deficiency

Vitamin D deficiency or failure to convert Vitamin D to Vitamin D3 will cause inadequate Calcium absorption from GI tract -Can occur from chronic renal failure -Children: Inadequate calcium absorption can cause *Rickets* -Adults: Inadequate calcium absorption can cause *osteomalacia*

Vitamins

Vitamins are required in small amounts to act as coenzymes or cofactors for various metabolic reactions -Vitamins are NOT synthesized in to body >Must be acquired from the fit and absorbed by the GI tract -Vitamins are either *fat-soluble* or *water-soluble*