Chapter 17 Fatty Acid Catabolism Acetyl CoA fates o Oxidized to CO2 in the citric acid cycle for energy conservation o In liver it may be converted to ketone bodies water soluble fuels exported to the brain and other tissues when glucose is not available o In higher plants it serves as a biosynthetic precursor a repetitive four step process by which fatty acids are Oxidation converted into acetyl CoA Because they are insoluble in water ingested triacylglycerols must be emulsified before they can be digested by water soluble enzymes in the intestine o Triacylglycerols absorbed in the intestine or mobilized from storage tissues must be carried in the blood bound to proteins that counteract their insolubility The complete oxidation of fatty acids to CO2 and H2O takes place in three stages o The oxidation of long chain fatty acids to two carbon fragments in the form of acetyl CoA oxidation o Oxidation of acetyl CoA to CO2 in the citric acid cycle o The transfer of electrons from reduced electron carriers to the mitochondrial respiratory chain 17 1 Digestion Mobilization and Transport of Fats Cells can obtain fatty acid fuels from three sources o Fats consumed in the diet o Fats stored in cells as lipid droplets o Fats synthesized in one organ for export to another Triacylglycerols are virtually the sole source of energy in hibernating animals Triacylglycerols provide more than half the energy requirements of some and migrating birds organs o Liver o Heart o Resting skeletal muscle Protists obtain fats by consuming organisms lower in the food chain and some store fats as cytosolic lipid droplets Vascular plants mobilize fats stored in seeds during germination Dietary Fats Are Absorbed in the Small Intestine Before being absorbed through the intestinal wall triacylglycerols must be solubilized into microscopic micelles by bile salts o Bile salts are synthesized from cholesterol in the liver stored in the gallbladder and released into the small intestine after ingestion of a fatty meal o Bile salts are amphipathic compounds that act as biological detergents converting dietary fats into mixed micelles of bile salts and triacylglycerols Lipase action converts triacylglycerols to monoacylglycerols and diacylglycerols free fatty acids and glycerol o Micelles are more accessible to lipases Apolipoproteins lipoprotein aggregates into which triacylglycerols are packed Chylomicrons after being converted back to this form in the intestine lipid binding proteins in the blood responsible for the transport of triacylglycerols phospholipids cholesterol and cholesteryl esters between organs Lipoprotein hydrophilic protein side chains and lipid head groups at the surface spherical aggregates with hydrophobic lipids at the core and o Apolipoproteins combine with lipids to form several classes of these Chylomicrons move from the intestinal mucosa into the lymphatic system and then enter the blood which carries them to muscle and adipose tissue o Lipoprotein lipase an extracellular enzyme activated by apoC II that hydrolyzes triacylglycerols to fatty acids and glycerol which are taken up by cells in the target tissues o In muscle fatty acids are oxidized for energy o In adipose tissue fatty acids are esterified for storage as triacylglycerols Hormones Trigger Mobilization of Stored Triacylglycerols Neutral lipids are stored in adipocytes as lipid droplets with a core of sterol esters and triacylglycerols surrounded by a monolayer of phospholipids Perilipins preventing untimely lipid mobilization a family of proteins that restrict access to lipid droplets o Coats the surface of lipid droplets Epinephrine and glucagon secreted in response to low blood glucose levels activate the enzyme adenylyl cyclase in the adipocyte plasma membrane which produces cAMP o CAMP dependent PKA phosphorylates perilipin A which causes hormone sensitive lipase to move to the lipid droplet surface where it hydrolyzes triacylglycerols to free fatty acids and glycerol Also phosphorylates hormone sensitive lipase increasing its Free fatty acids activity FFA fatty acids released from lipid droplets o Pass from the adipocyte into the blood where they bind to serum albumin which carries them to other tissues Glycerol kinase phosphorylates the glycerol released by lipase action forming glycerol 3 phosphate which is oxidized to dihydroxyacetone phosphate o Triose phosphate isomerase converts dihydroxyacetone phosphate to glyceraldehyde 3 phosphate which is oxidized via glycolysis Fatty Acids Are Activated and Transported into Mitochondria The enzymes of fatty acid oxidation are located in the mitochondrial matrix Fatty acids with 14 or more carbons cannot pass directly through the mitochondrial membranes they must first undergo three enzymatic reactions of the carnitine shuttle o Esterification to CoA Acyl CoA synthetases catalyze the formation of a thioester linkage between the fatty acid carboxyl group and the thiol group of coenzyme A to yield fatty acyl CoA Coupled to the cleavage of ATP to AMP and PPi Two steps Involves a fatty acyl adenylate intermediate Fatty acyl CoAs are high energy compounds o Transesterification to carnitine followed by transport Fatty acids are transiently attached to the hydroxyl group of carnitine to form fatty acyl carnitine Catalyzed by carnitine acyltransferase I in the outer membrane The fatty acyl carnitine ester then enters the matrix by facilitated diffusion through the acyl carnitine carnitine transporter of the inner mitochondrial membrane o Transesterification back to CoA The fatty acyl group is enzymatically transferred from carnitine to intramitochondrial coenzyme A by carnitine acyl transferase II an isozyme located on the inner face of the inner mitochondrial membrane that regenerates fatty acyl CoA and releases it along with carnitine into the matrix Coenzyme A in the mitochondrial matrix is largely used in oxidative degradation of pyruvate fatty acids and some amino acids Cytosolic coenzyme A is used in the biosynthesis of fatty acids Fatty acyl CoA in the cytosolic pool can be used for membrane lipid synthesis as well 17 2 Oxidation of Fatty Acids Three stages o Oxidation fatty acids undergo oxidative removal of successive two carbon units in the form of acetyl CoA starting from the carboxyl end of the fatty acyl chain o The acetyl groups of acetyl CoA are oxidized to CO2 in the citric acid cycle in the mitochondrial matrix o First two stages produce NADH and FADH2 which donate electrons
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