BIOC Dr. Tischler Lecture 28 March 23, 2005 LIPIDS: DIGESTION AND ABSORPTION. Tucson

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1 BIOC Dr. Tischler Lecture 28 March 23, 2005 LIPIDS: DIGESTION AND ABSORPTION Tucson

2 FAT FACTS Fat (lipid) makes up 37% of the calories in the American diet Fat is energy rich and provides 9 kcal/gm Dietary lipids are 90% triacylglycerols; also include cholesterol esters, phospholipids, essential unsaturated fatty acids; fat soluble vitamins (A,D,E,K) Normally essentially all (98%) of the fat consumed is absorbed, and most is transported to adipose for storage.

3 SIX STEPS OF LIPID DIGESTION AND ABSORPTION Minor digestion of triacylglycerols in mouth and stomach by lingual (acidstable) lipase Major digestion of all lipids in the lumen of the duodenum/jejunum by pancreatic lipolytic enzymes Bile acid facilitated formation of mixed micelles that present the lipolytic products to the mucosal surface, followed later by enterohepatic bile acid recycling Passive absorption of the lipolytic products from the mixed micelle into the intestinal epithelial cell Reesterification of 2-monoacylglycerol, lysolecithin, and cholesterol with free fatty acids inside the intestinal enterocyte Assembly and export from intestinal cells to the lymphatics of chylomicrons coated with Apo B48 and containing triacylglycerols, cholesterol esters and phospholipids

4 Lipids: Triacylglycerols Cholesterol esters Phospholipids Lingual Lipase 1a FFA + DAGs (miniscule amounts) MOUTH EXOCRINE PANCREAS Bile Acid synthesis & conjugation trypsinogen, procolipase, lipase, esterase, HCO 3-, propla 2 CCK-PZ stimulates secretion Bile Salt storage GALL BLADDER CCK-PZ causes contraction Triacylglycerols FFA Trypsinogen Trypsin Enteropeptidase Lingual Lipase ("acid-stable") Triacylglycerol Droplet 1b Endocrine cell FFA + DAGs (small amounts) STOMACH CCK-PZ via bloodstream + B48 SMALL INTESTINE duodenum/jejunum 6b LIVER Enterohepatic circulation of bile acids 3b Portal vein ProPLA 2 Phospholipid (with essential unsaturated FAs) esterase Trypsin PLA 2 2b 2c + bile acids, Ca 2+ Cholesterol ester Cholesterol + FFA Procolipase + bile acids 3a Lysolecithin +FFA lipase Trypsin 3a Reabsorbed by ileum Colipase 3a FFA + 2MG 2a Coalescence into micelles Stabilized by bile acids 4 Mixed Micelles: 2MG, FFA, lysolecithin, cholesterol, vitamins A,D,E,K Released bile acids 3b vitamins Chylomicron D, E, K Coating with 6a apolipoprotein (with TTP) Triacylglycerol FFA, 2MG 5 Short/medium chain FFA Cholesterol ester Phospholipid reesterification ACAT cholesterol lysolecithin vitamin A

5 Table 1. Summary of the physiologically important lipases Lipase lingual/acidstable lipase pancreatic lipase milk lipase phospholipase A 2 (PLA 2 ) lipoprotein lipase Hormone-sens. Lipase Site of Action mouth, stomach small intestine small intestine small intestine capillary walls Regulation Preferred Substrate ---- TAGs with med. chain FAs colipase (+) TAGs with longchain FAs bile acids (+) TAGs with med. chain FAs bile acids (+) Ca 2+ (+) apo CII (+) insulin (+) adipose cell insulin (-) glucagon (+) Epineph. (+) PLs with unsat. FA on position 2 TAGs in chylomicron or VLDL TAG stored in adipose cells C cleaved Product(s) 3 FFA+DAG 1 and 3 FFA+2MG 1 and 2 and 3 FFA+ glycerol 2 Unsat FFA lysolecithin 1 and 2 and 3 FFA+ glycerol 3 FFA+DAG

6 Lipids: Triacylglycerols Cholesterol esters Phospholipids Lingual Lipase 1a FFA + DAGs (miniscule amounts) MOUTH Triacylglycerols Lingual Lipase ("acid-stable") 1b FFA + DAGs (small amounts) STOMACH STEP 1: Digestion in the Mouth and Stomach

7 EXOCRINE PANCREAS trypsinogen, procolipase, lipase, esterase, HCO 3-, propla 2 CCK-PZ stimulates secretion from stomach FFA Trypsinogen Endocrine cell CCK-PZ via bloodstream Bile Acid Synthesis Conjugation LIVER Bile Salt storage GALL BLADDER Procolipase lipase SMALL INTESTINE duodenum/jejunum CCK-PZ causes contraction ProPLA 2 esterase STEP 2: Enzymatic Digestion in the Duodenum/Jejunum secretion of zymogens/bile salts

8 FFA Trypsinogen Enteropeptidase Trypsin Endocrine cell CCK-PZ via bloodstream + SMALL INTESTINE duodenum/jejunum STEP 2: Enzymatic Digestion in the Duodenum/Jejunum activation of trypsinogen

9 Triacylglycerol Droplet Procolipase lipase Trypsin catalyzed activation Colipase FFA + 2MG 2a 2b esterase Cholesterol ester + bile acids Cholesterol + FFA ProPLA 2 Trypsin catalyzed activation 2c Phospholipid (with essential unsaturated FAs) PLA 2 + bile acids, Ca 2+ Lysolecithin +FFA STEP 2: Enzymatic Digestion in the Duodenum/Jejunum pancreatic lipase (2a), esterase (2b) and phospholipase A 2 (2c)

10 Bile Acids pk a = 5 Conjugated Bile Acids Primary (synthesized in liver from cholesterol) Chenodeoxycholic Acid Cholic Acid Glycoconjugates pk a = 3.7 +glycine Secondary (formed by bacterial dehydroxylation in intestinal lumen) Deoxycholic Acid +taurine Tauroconjugates pk a = 1.5 Figure 2. Bile acids. The pka is lowered by formation of conjugates in liver. Conjugated acids more easily remain ionized in the intestine.

11 Cholesterol + FFA Lysolecithin +FFA 3a 3a FFA + 2MG 3a Coalescence into micelles Stabilized by bile salts; lower pka of bile salt vs bile acid maintains it in ionized form Mixed Micelles: 2MG, FFA, lysolecithin, cholesterol, vitamins A,D,E,K STEP 3a: Bile Acid Facilitated Formation of Mixed Micelles

12 LIVER SMALL INTESTINE duodenum/jejunum Enterohepatic circulation of bile acids 3b Portal vein Mixed Micelles 4 3b Released bile acids FFA, 2MG Short/medium chain FFA cholesterol lysolecithin vitamin A Reabsorbed by ileum STEP 3b: Bile Acid Recycling STEP 4: Lipid Absorption Capillaries

13 SMALL INTESTINE duodenum/jejunum Triacylglycerol transfer protein 6a B48 Chylomicron Triacylglycerol 6b Coating with apolipoprotein (with TTP) vitamins D, E, K Cholesterol ester Phospholipid To lacteals and thoracic duct STEP 5: Re-esterification STEP 6: Chylomicron Assembly and Export reesterification FFA, 2MG 5 ACAT cholesterol lysolecithin vitamin A Acyl CoA: cholesterol acyl transferase

14 DIET (carrots) Figure 3. VITAMIN A PROCESSING -Carotene Irreversible oxidative cleavage in Intestinal Cell Retinaldehyde (Retinal; required for vision) NADPH reduction in intestine DIET esterase Retinol esters (liver/dairy) esterified intestinal cell to liver in chylomicrons remnants vitamin A metabolism: oxidation in eye, epithelial cells Retinol (vitamin A) for reproduction Retinol palmitate stored in liver hydrolyzed in liver blood transport via RBP vitamin A metabolism: irreversible oxidation in epithelial cells all-trans retinoic acid growth, differentiation, maintaining epithelial tissues vitamin A metabolism: retinoic acid isomerase 9-cis retinoic acid

15 CLINICAL CORRELATES Orlistat (Xenical) anti-obesity drug inhibits pancreatic and gastric lipase blocks about 30% of dietary fat from digestion and absorption Olestra artificial fat chemical structure is a sucrose polyester esterified with 8 fatty acids not digested by gastric or pancreatic lipases (or sucrase) passes through the system undigested and unabsorbed in excess interferes with absorption of fat-soluble vitamins