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Biochemistry Ch 32 585-596 Digestion and Transport of Dietary Lipids Digestion of Triacylglycerols – triacylglycerols are the major fat in human diet; they contain a glycerol backbone + 3 fatty acids -digestion involves hydrolysis to fatty acids and 2-monoacylglycerol in the intestine -depends on the length of fatty acid chains -lingual/gastric lipases hydrolyze short + medium chain fatty acids (<12C) -mammary gland produces milk, which contains long-chain fatty acids Action of Bile Salts – fat enters small intestine and is emulsified by bile salts, which are amphipathic compounds synthesized by liver and secreted by gallbladder -CCK stimulates contraction of gallbladder and bile salt secretion -bile salts bind globules of fat as they are broken up by peristalsis in intestine -emulsified fat is attached by digestive enzymes from pancreas Action of Pancreatic Lipase – secreted along with another protein, colipase in response to CCK -secretin is released by intestine in response to acidic materials -secretin signals liver, pancreas, and intestinal cells to secrete HCO3 to raise pH of intestine for action of intestinal digestive enzymes -Bile salts INHIBIT pancreatic lipase by coating substrate and not allowing access to enzyme -Colipase binds dietary fat and to lipase to relieve inhibition and enhances lipase activity -Pancreatic lipase then hydrolyzes fatty acids of ALL chain lengths from positions 1 and 3 of glycerol to produce free fatty acids and 2-monoacylglycerol w/ fatty acid at position 2 -pancreas also produces esterases that remove fatty acids from compounds and PLA2 that digests phospholipids to a free fatty acid and lysophospholipid Absorption of Dietary Lipids – fatty acids and 2-monoacylglycerols, also cholesterol, vitamins, etc. are packaged into micelles and emulsified by bile salts (concentration needs to be 5-15mM) -micelles travel through layer of water to microvilli on surface of intestinal cells, where the fatty acids, 2-monoacylglycerol, and other lipids are absorbed, but bile salts are NOT ABSORBED -Bile salts are reabsorbed in the ILEUM and travel back to liver, which secretes them again -short/medium chain fatty acids (C4-12) do NOT NEED bile salts for absorption -transported to liver bound to serum albumin Synthesis of Chylomicrons – inside intestinal epithelium, fatty acids and 2-monoacylglycerols are converted back to triacylglycerols in sER enzymatic reactions -fatty acids are activated to fatty acyl-CoA and reacts with 2-monoacylglycerol diacylglycerol, which reacts with another fatty acyl-CoA to form a triacylglycerol -triacylglycerols are transported in lipoproteins because they are insoluble in H2O, and so intestine cells package triacylglycerols with proteins and phospholipids into chylomicrons which contains cholesterol and fat-soluble vitamins, but MAJOR COMPONENT is triglyceride -protein component of lipoproteins are known as apoproteins -Major apoprotein in chylomicrons is apoB-48, which is related to B-100 which is synthesized in liver and is found in VLDLs; both encoded by same gene, apoB-48 undergoes RNA editing to 48% of the size of B-100 -protein component of lipoproteins synthesized in rER, and lipids in sER -Olestra is fat substitute without calories from fat (sucrose with fats), and cannot be digested Transport of Dietary Lipids in Blood – chylomicrons secreted by intestinal epithelial cells into chyle of lymphatic system enter blood through thoracic duct -chylomicrons enter blood 1-2 hours after start of a meal -they are called nascent chylomicrons until receiving proteins from HDL, becoming “mature” -HDLs transfer proteins such as apoE and apoCII -apoE is recognized by membrane receptors on liver cells for endocytosis/degradation -apoCII activates lipoprotein lipase (LPL), an enzyme on capillary endothelial cells within muscle and adipose to digest triacylglycerols on chylomicrons and VLDL in blood -chylomicrons are the least dense of all of the lipoproteins Fate of Chylomicrons – triacylglycerols on chylomicrons are digested by LPL attached to proteoglycans in basement membranes of endothelial cells that line capillary walls -LPL is produced by adipose cells, muscle, and lactating mammary gland -adipose LPL has higher Km than muscle, therefore adipose LPL is more active after a meal, when chylomicron levels are elevated in the blood -INSULIN increases levels of LPL synthesis from adipose after a meal to facilitate digestion -fatty acids released from triacylglycerols by LPL are not soluble, but become attached to albumin -major fate of fatty acids is storage as triacylglycerol in adipose tissue, but can also be oxidized for energy in muscle and other tissues -since muscle LPL has lower Km, muscle obtains fatty acids from blood whenever they are needed for energy, even if concentration of lipoproteins is low -glycerol released from chylomicron triacylglycerols by LPL used for liver triacylglycerol synthesis -portion of chylomicron that remains in blood after LPL action is known as a chylomicron remnant, which has LOST apoC molecules, which exposes apoE and binds to liver for degradation by lysosomes -People can lose weight by inhibiting pancreatic lipase which results in fat digestion and absorption -orlistat is a drug that is derivative of lipstatin, a lipase inhibitor in bacteria -Heparin is polysaccharide component of proteoglycans used as an anticoagulant by binding to antithrombin III and activating to inhibit clotting factors -heparin binds LPL on capillaries to dislodge it, and loss of activity increases blood lipids Microsomal Triglyceride Transfer Protein – required for assembly of chylomicrons within ER of enterocyte -a subunit called Protein Disulfide Isomerase (PDI) has a role that is not known -bigger subunit contains triglyceride transfer activity, and MTP accelerates transport of triglycerides, cholesterol esters, and phospholipids across membranes of subcellular organelles -lack of this enzyme leads to abetalipoproteinemia – affects chylomicron assembly in the intestine and VLDL assembly in the liver -both particles require B apoprotein for assembly (B-48 and B-100), since MTP binds B apoproteins -MTP activity is necessary to transfer triacylglycerol formed within ER to apoB protein -symptoms of abetalipoproteinemia include lipid malabsorption, caloric deficiencies, etc.. -MTP inhibitors have been investigated for their role on circulating lipid and cholesterol levels