Summary of key points of the lecture

• Six steps of lipid digestion/absorption:

o 1. minor digestion of TAGs in mouth/stomach

o 2. major digestion of lipids in the duodenum/jejunum by pancreatic enzymes

o 3. bile acid facilitated micelle formation

o 4. passive absorption of lipolytic products from the micelle into the intestinal epithelial cell

o 5. reesterification to form cholesterol ester and TAGs

o 6. assembly and export of chylomicrons to lymphatics

• Lingual/acid-stable lipase in mouth/stomach removes one medium chain fatty acid from TAGs

• Milk lipase, activated by bile acids in small intestine, removes medium chain FAs from milk TAGs

• Pancreatic lipase, activated by colipase, removes 2 long chain fatty acids from TAGS leaving 2MG

• The inactive form of colipase (pancreatic procolipase) is activated by trypsin in the intestinal lumen

• The zymogen form of phospholipase A2 is released from the pancreas, activated by trypsin and then removes unsaturated fatty acids from phospholipids - requires bile acids and calcium

• CCK-PZ responds to free fatty acids and signals exocrine pancreas to release trypsinogen,

procolipase, lipase, cholesterol esterase and epithelial cells to release enteropeptidase

• Secretin causes the pancreas to release bicarbonate to neutralize stomach acid

• Bile acids formed from cholesterol in the liver; then conjugated with glycine or taurine to lower their pKa to allow them to form salts in the intestinal lumen

• Bile acids, released from the gall bladder in response to CCK-PZ, emulsify lipids to facilitate their incorporation into mixed micelles

• Mixed micelles deposit lipids for absorption into the intestinal cells; bile acids are released and some reenter the circulation from the ileum (enterohepatic circulation) for liver reuptake and excretion

• Re-esterification in intestinal mucosal cells leads to formation of TAGs (from long chain FAs and 2MG), cholesterol ester, and phospholipids; with fat-soluble vitamins incorporated into chylomicrons

• Chylomicrons formed with apoprotein B48 and aided by triacylglycerol transfer protein (TTP) are then exported to the lymphatics

• Unlike long chain fatty acids reesterified into TAGs, medium and short chain fatty acids enter directly into the circulation from the intestinal cell

• Olestra - artificial fat replacement - cannot be processed/absorbed; reduces lipid absorption by

binding and excreting lipids

• Orlistat - drug that blocks the digestion and absorption of about 30% of dietary fats

• Vitamin A is absorbed via mixed micelles and then incorporated into chylomicrons

• Retinal is oxidized in intestinal cells from β-carotene and reduced to retinol that is also from the diet

• Vitamin A is stored as retinol palmitate in the liver

• Stored vitamin A can be mobilized and transported as retinol to be oxidized in other tissues to retinal

• Retinal is used directly for vision or in some cells is oxidized further to all-trans retinoic acid and then converted to 9-cis retinoic acid

• Retinal formed from dietary vitamin A can also be directly used or oxidized

• all-trans retinoic acid is used for growth, differentiation and maintaining epithelial tissues

  1. With regard to lipid digestion and absorption

Aside from making them soluble lipid assimilation is that hydrolyzing large non absorbable molecules into smaller units

a)list the six general steps

1. Minor digestion of triacylglycerols in the mouth and stomach by lingual (acid-stable) lipase

2. Major digestion of all lipids in the lumen of the duodenum/jejunum by pancreatic lipolytic enzymes

3. Bile acid facilitated formation of mixed micelles that present the lipolytic products to the mucosal surface, followed later by enterohepatic bile acid recycling

4. Passive absorption of the lipolytic products from the mixed micelle into the intestinal epithelial cell

5. Reesterification of 2-monoacylglycerol, lysolecithin, and cholesterol with free fatty acids inside the intestinal enterocyte

6. Assembly and export from intestinal cells to the lymphatics of chylomicrons coated with Apo B48 and containing triacylglycerols, cholesterol esters and phospholipids

b) for the physiologically important lipases, identify their anatomical sites of action,

substrates, products, and regulation, where relevant.

c) describe the actions of the intestinal hormones, cholecystokinin-pancreozymin (CCKPZ)

and secretin.

  • Entry of acid chyme & free fatty acids into duodenal lumen stimulates endocrine cells to release CCK – PZ into bloodstream
  • CCK –PZ binds to its G protein linked receptor on the gall bladder CCK-A causing contraction & hence release of bile salts into intestinal lumen
  • CCK-PZ binding in human pancreas to G protein linked CCK-B receptors causes secretion into the intestinal lumen of digestive enzymes eg. Trypsinogen
  • CCK also elicts the release of enteropeptidase into the lumen where it activates trypsin from trypsinogen
  • Secretin causes the pancreas to secrete bicarb rich fluid that neutralizes the gut lumen
  • Major enzyme for Triacyglycerol hydrolysis is pancreatic lipase specific for esters in #1 & #3 position of glycerol & prefers to hydrolyze esterfied long chain faty acids>12 → products free fatty acids (FFA) & 2 monoacylglycerols (2MG)
  • Purified form of the pancreatic lipase enzyme is strongly inhibited by bile acids that are normally present in the small intestine → problem of inhibition is overcome colipase . Secreted as procolipase & depends on trypsin for activation
  • Milk Lipase hydrolyzes fats from all 3 positions, it is enhanced by low concentrations of bile acids
  • Pancreatic Juice also contains a non specific pancreatic esterase or cholesterol esterase which acts on cholesterol esters→ activated directly by bile acids
  • Intake of phospholipids is low compard to TAG but these lipids often contain essential fatty acids. They are hydrolyzed by specific phopholipases. Panc. Secretions are especially rich in the proenzyme for phospholipase A2→ activated by trypsin. Needs both bile acids & Ca

d) describe the synthesis, modification, secretion, reabsorption and recirculation of bile

acids and their role in lipid absorption.

Bile Acids

  • Synthesized exclusively in the liver from cholesterol, stored in gall bladder as bile salts & secreted in the duodenum to form micelles
  • Rate limiting step is of bile acids from cholesterol is the introduction of a hydroxyl group by 7α-hydroxylase.
  • Important also is 12αhydroxylation and side chain oxidation to carb group
  • Secondary bile acids are from primary bile acids by bacterial action
  • Within the liver primary & secondary bile acids conjugate to either glycine or taurine via amide bond→ glycol- & tauro-conjugates main forms of bile secreted. Bile Acids and their conjugates exist in the bile as Na & K salts→ these are stored in the gall bladder therefore bile acids are referred to as bile salts
  • Shortly after a meal, bile salts from the gallbladder & liver are released into the lumen, pass with chyme down SI are reabsorbed by the epithelium of the lower SI into the portal blood and extracted by liver cells. Secretion & reuptake is enterohepatic circulation

e) explain how fatty acids, 2-monoacylglycerols, cholesterol and lysophospholipids are

absorbed into the intestinal mucosa, reesterified and exported in chylomicrons.

  • Mixed micelles deposit lipids for absorption by reversibly forming micelles
  • Arrangement of amphipathic bile acids in micelles the hydrophobic are removed fom contact with water while hydrophilic (hydroxyls & carboxylates) remain exposed to water
  • Bile acids form micelles with other lipids, such as 2 monoacylglycerol, phospholipids,FA and fat soluble vitamins
  • Micelles provide the major vehicle for moving lipids from the intestinal lumen to the cell surface where absorption occurs
  • The efficiency of lipid absorption depends on the presence of sufficient bile acids to “solubilize” the hydrolyzed ingested lipids in micelles and present them to the cell surface for absorption
  • Uptake of lipids by epithelial cells occurs passively. Virtually all complete for fatty acids & 2 monoacylglycerols which are slightly water soluble
  • Micelles remain behind to solubilize other lipid products like a shuttle
  • Bile acids are not absorbed at this point travel length of SI are absorbed in the terminal ileum by ATP requiring active transport process
  • Re-esterfication in intestinal mucosal cells leads to formation of TAG (from long chain fatty acid’s & 2MG), cholesterol ester, & phospholipids with fat soluble vitamins incorporated into chylomicrons

2. Contrast the fates and routes in the body taken by long-chain fatty acids with that taken by

short-chain and medium-chain fatty acids.

  • Fatty acid of medium chain length 6-12 pass through the cell into the portal blood without modification
  • Long chain fatty acids become bound to a cytoplasmic intestinal fatty acid binding protein & are transported to the smooth ER where they are re-esterified into triacylglcerols. Glycerol is derived from the absorbed 2-monoacylglycerols
  • Short and medium chain fatty acids reach the liver directly via portal blood but the long chain fatty acids bypass the liver by being released in the form of chylomicrons into the lymphatic system

3. Describe the mechanisms whereby Olestra supplants and orlistat reduces lipid absorption.

4. Describe the absorption and steps in the metabolism of vitamin A, and the general roles of the

individual vitamin A metabolites.

1