1Lipid MetabolismReview Fatty AcidsTriglycerides/TriacylglyerolStorage form of fatty acidPhospholipidsOxidation of Fatty Acids to Acetyl CoAEnergy yieldingliver, heart, resting skeletal muscle--50% of energy from fatBiosynthetic precursorsGlucose in plantsketone bodies in animalsTriacylglycerols (triglycerides) are the most abundant dietary lipids, & the form in which we store reduced carbon for energy. Each triacylglycerol has a glycerol backbone to which is esterified 3 fatty acids. Most are mixed, with different fatty acids varying in chain length & double bonds.2Triacylglycerols (triglycerides) are the most abundant dietary lipids, & the form in which we store reduced carbon for energy. Each triacylglycerol has a glycerol backbone to which is esterified 3 fatty acids. Most are mixed, with different fatty acids varying in chain length & double bonds. glycerol fatty acid triacylglycerol H2CHCH2COHOHOHH2CHCH2COOOCROCCROROHO C RO3A 16-C fatty acid, with numbering conventions, is shown. Most naturally occurring fatty acids have an even number of carbon atoms.The pathway for catabolism of fatty acids is referred to as the β-oxidation pathway, because oxidation occurs at the β-carbon (C-3).COO−1234αβγ fatty acid with a cis-∆9double bond4Source of Fatty acid fuels1. Digestion and absorption in gastrointestinal tractResynthesis of triacylglycerols and transport via lymph as chylomicrons2. De novo synthesized fatty acids in livertransport in VLDL to adipose tissue for storage3. Mobilization of triacylglyercide from adipose tissue5Pathway for dietary lipid intake in vertebratesDigestion & transport of lipids poses unique problems relating to the insolubility of lipids in water. Enzymes that act on lipids are soluble proteins or membrane proteins at the aqueous interface. Lipids, and products of their digestion, must be transported through aqueous compartments within the cell as well as in the blood & tissue spaces.Lipases hydrolyze triacylglycerols, releasing 1 fatty acid at a time, yielding diacylglycerols, & eventually glycerol. Free fatty acids, which in solution have detergent properties, are transported in the blood bound to albumin, a serum protein produced by liver.6Bile acids (bile salts) are polar derivatives of cholesterol, formed in liver and secreted into the gall bladder. They pass via the bile duct into the intestine, where they aid digestion of fats & fat-soluble vitamins. Bile acids are amphipathic, with detergent properties. OHCH3CH3COO R2R1HOR1 = OH or HR2 = H or NH−CH2−COOH or NH−CH2−CH2−SO3−H Bile Acids Conversion to bile salts, that are secreted into the intestine, is the only mechanism by which cholesterol is excreted. Most bile acids are reabsorbed, returned to the liver by the portal vein, and re-secreted. This is the enterohepatic cycle. Agents that interrupt this cycle, by binding bile acids (&/or cholesterol) preventing absorption/reabsorption, are used to treat high blood cholesterol. E.g., synthetic resins, and soluble fiber (oat bran fiber & fruit pectin).7CHOCH2OH2COCR1OPOOO−XCHHOCH2OH2COCR1OPOOO−X+H2OCR2OO−CR2Ophospholipidlysophospholipid fatty acidH2CHCH2COOOCR1OCCR3OR2O−OCR3OH2CHCH2COOOHCR1OCR2OH2Otriacylglycerol 1,2-diacylglycerol fatty acid+Pancreatic lipasePhospholipase A2Pancreatic lipase (secreted into the intestine), catalyzes hydrolysis of triacylglycerols at their 1 & 3 positions, forming 1,2-diacylglycerols, & then 2-monoacylglycerols (monoglycerides). The protein colipase is required to aid binding of the enzyme at the lipid-water interface.Monoacylglycerols and fatty acids are absorbed by intestinal epithelial cells. Within intestinal epithelial cells triacylglycerols are resynthesized. Phospholipase A2is secreted by the pancreas into the intestine. It hydrolyzes the ester linkage between the fatty acid & the hydroxyl on C2 of phospholipids. Lysophospholipids, the products of Phospholipase A2reactions, are powerful detergents.Lysophospholipids, produced from phospholipids via Phospholipase A2, aid digestion of other lipids by breaking up fat globules into small micelles. Some phospholipid (lecithin) is secreted by the liver in the bile, presumably to provide substrate for Phospholipase A2within the intestine and thus aid in fat digestion. Cobra & bee venoms contain Phospholipase A2. These venoms, injected into the blood, produce lysophospholipids that disrupt cell membranes and lyse blood cells.8Fatty acid-binding proteins, which are in several cell types, have a ''β-clam" structure. A fatty acid is carried in a cavity between 2 approx. orthogonal β-sheets, each consisting of 5 antiparallel β-strands. I-FABP PDB 1ICM Within intestinal cells, fatty acids (which are poorly soluble and have detergent properties) are kept sequestered from the cytosol by being bound with intestinal fatty acid binding protein (I-FABP).9Chylomicron structureMost other lipids are transported in the blood as part of lipoproteins, complex particles whose structure includes:a core consisting of a droplet of triacylglycerols and/or cholesteryl estersa surface monolayer of phospholipid, cholesterol, & specific proteins (apolipoproteins), e.g., B-100.Intestinal epithelial cells synthesize triacylglycerols, cholesteryl esters, phospholipids, free cholesterol, and apoproteins, and package them into chylomicrons. Chylomicrons are secreted by intestinal epithelial cells, and transported via the lymphatic system to the blood.Apoprotein CII on the chylomicron surface activates Lipoprotein Lipase, an enzyme attached to the lumenal surface of small blood vessels. Lipoprotein Lipase catalyzes hydrolytic cleavage of fatty acids from triacylglycerols of chylomicrons. Released fatty acids & monoacylglycerols are picked up by body cells for use as energy sources.10Mobilization of triacylglycerolsstored in adipose tissueFree fatty acids are transported in the blood bound to albumin, a serum protein secreted by liver.Perilipins surround lipid droplets and prevent premature or untimed lipid mobilization. PKA phosphorylates (1) perlipin and causes it to allow HSL access to the TAGs(2) HSL and causes it to move to the lipid droplet.(3) Phosphorulates HSL and increases activity of the enzymeA defect in perlipin genes, no increase in FA mobilization when c AMP levels are increased. HSL is not able to access the Triacylglycerides.11Knoop Experiment -- 1904Concluded: 2 oxidized at a