Lipid Metabolism SOM 610 PDF

Absorptive (fed) state Fats are a great source of energy but how do you absorb and store an insoluble compound? The solution: chew, emulsify, break-down, import, package, transport, break-down(2), import(2) , package(2), store. 2  You eat mostly triacyl...

Absorptive (fed) state Fats are a great source of energy but how do you absorb and store an insoluble compound? The solution: chew, emulsify, break-down, import, package, transport, break-down(2), import(2) , package(2), store. 2  You eat mostly triacylglycerol phospholipids and cholestryl esters – not very soluble! Lipases play a key role Acid lipases: 1) Lingual (back of tongue) 2) Gastric Pancreatic lipase Lipoprotein lipase 3 4...chew… Lingual (back of tongue) and gastric (stomach) lipases preferentially hydrolyze triacylglycerols with short and medium FAs (12 or fewer carbons). - pH optimum pH 4 to pH 6 - Important in those with pancreatic insufficiency (such as in cystic fibrosis) - Important in neonates… 5...emulsify… - Emulsification takes place in small intestine (duodenum) - Goal is to increase surface area of lipid blobs for digestive enzymes - Accomplished by peristalsis and bile salts 6...emulsify… Bile salts help form micelles that contain TG. Made from cholesterol in liver and secreted from gall bladder. 7  …break-down... Pancreatic enzymes are key: - Pancreatic lipase - Cholesterol esterase - Phospholipase A2 Secretion under hormonal control 8 9...break-down… Pancreas secretes bicarbonate (HCO3-) and colipase. HCO3- neutralizes acid that enters the intestine from the stomach and thus provides a pH which is optimal for digestive enzymes of the intestine. Colipase binds to the fat and the lipase, facilitating lipase activity. 10...break down… Hormonal control Cholecystokinin (CCK) Secreted by cells in jejunum and lower duodenum Acts on gallbladder and pancreas Acts on stomach Induces satiety Secretin Acts on pancreas to release bicarbonate 11  …import… The primary products of dietary lipid degradation in the jejunum are: Free fatty acids Free cholesterol 2-monoacylglycerol These products plus bile salts yield micelles, which cozy up to mucosal cells. 12  …import… Mixed micelles are soluble Short- and medium- chain fatty acids do not need micelles to be absorbed by mucosal cell. 13  …package… Takes place in ER Short- and medium-chain fatty acids can zip into portal circulation, carried to liver by serum albumin. 14 …transport, break-down(2)…  Lipoprotein Lipase (LPL) Produced by adipose cells, muscle cells, and lactating mammary tissue Released (secreted) from cells, becomes attached to basement membranes of endothelial cells lining capillary walls Extracellular - bound to proteoglycans Acts on TG of chylomicrons and VLDL to release FA and glycerol Activated by ApoCII 17  …import(2) , package(2), store. TAG Chylomicron remnants deliver dietary cholesterol to liver!  High fat Very high fat Then cheese- Then cheese- cake 30 min cake 30 min Lunch: Fast before sample before sample Note the increase in turbidity of upper yellow layer from left to right. This is. caused by chylomicrons. Note that people who ate 1 hour before blood sample have cleared a good bit of their fat. Don’t let this freak you out. Enjoy the holidays, just don’t drink a gallon of eggnog per day. 19  Steatorrhea Poop is frothy, foul-smelling and floats (difficult to flush) because of high fat content. Can be caused by problems with lipase from pancreas or bile from liver. Chronic pancreatitis Blockages in pancreatic or bile ducts can lead to steatorrhea, ex. cystic fibrosis Decreased fat soluble vitamin (A, D, E, and K) and essential fatty acid absorption. Absorptive (fed) state 21 Palmitic acid (Palmitate) 16 carbon fatty acid. Precursor to all other fatty acids (except essential fatty acids: linoleic acid and linolenic acid) Don’t forget, cis double bands more common than trans. Also cis double bonds are kinky. 22  Overview of Fatty Acid Synthesis Acetyl CoA + ATP + NADPH + H+ Palmitate + CoA + ADP + Pi + H20 + NADP+ Takes place primarily in the cytoplasm of liver and lactating mammary glands and, to a lesser extent, adipose tissue. 23 First problem – get acetyl CoA to cytoplasm Citrate-malate shuttle Pyruvate Pyruvate carboxylase dehydrogenase Citrate synthase 24  Citrate/malate shuttle accomplishes two things: 1.Gets acetyl CoA to cytoplasm where it can be used for FA synthesis. 2.Generates NADPH, which is the reductant for FA synthesis (also get NADPH from pentose phosphate pathway). 25 Rate-limiting step in fatty acid synthesis High insulin/low glucagon stimulates the synthesis and activity of the enzyme Citrate promotes the formation of active polymers from inactive dimers Palmitoyl CoA inhibits activity of the enzyme 26 29 Malonyl CoA inhibits carnitine shuttle. Prevents newly synthesized fatty acids from being quickly oxidized. Thus no futile cycle. 30 End product of FA synthase reaction is palmitate (16:0) Can be elongated two carbons at a time in endoplasmic reticulum Rxns similar to FA synthase, require malonyl CoA, NADPH Can also be elongated in mitochondria Brain can make very-long-chain FAs (up to 24 carbons) 31  Human desaturases cannot introduce double bonds between the w carbon and the seventh carbon from the w end, thus we need: 32 Synthesis of Triacylglycerols 33 Synthesis of Triacylglycerols Get glycerol phosphate via: 1) DHAP (liver and adipose) 2) glycerol (liver only) 34 36 Absorptive (fed) state 37  Integration of lipid and carbohydrate metabolism For example: High insulin/Low glucagon Pyruvate dehydrogenase in mitochondria stimulated by dephosphorylation Synthesis of citrate lyase, malic enzyme, glucose 6-phosphate dehydrogenase, and FA synthase induced Therefore, insulin promotes lipogenesis 38 High insulin/low glucagon 39