Harpers

OXIDATION OF FATTY ACIDS: KETOGENESIS / 189feeding and after severe exercise in the postabsorptivestate.SUMMARY• Fatty acid oxidation in mitochondria leads to the generationof large quantities of ATP by a process calledβ-oxidation that cleaves acetyl-CoA units sequentiallyfrom fatty acyl chains. The acetyl-CoA is oxidized inthe citric acid cycle, generating further ATP.• The ketone bodies (acetoacetate, 3-hydroxybutyrate,and acetone) are formed in hepatic mitochondriawhen there is a high rate of fatty acid oxidation. Thepathway of ketogenesis involves synthesis and breakdownof 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by two key enzymes, HMG-CoA synthase andHMG-CoA lyase.• Ketone bodies are important fuels in extrahepatic tissues.• Ketogenesis is regulated at three crucial steps: (1)control of free fatty acid mobilization from adiposetissue; (2) the activity of carnitine palmitoyltransferase-Iin liver, which determines the proportion ofthe fatty acid flux that is oxidized rather than esterified;and (3) partition of acetyl-CoA between thepathway of ketogenesis and the citric acid cycle.• Diseases associated with impairment of fatty acid oxidationlead to hypoglycemia, fatty infiltration of organs,and hypoketonemia.• Ketosis is mild in starvation but severe in diabetesmellitus and ruminant ketosis.REFERENCESEaton S, Bartlett K, Pourfarzam M: Mammalian mitochondrial β-oxidation. Biochem J 1996;320:345.Mayes PA, Laker ME: Regulation of ketogenesis in the liver.Biochem Soc Trans 1981;9:339.McGarry JD, Foster DW: Regulation of hepatic fatty acid oxidationand ketone body production. Annu Rev Biochem1980;49:395.Osmundsen H, Hovik R: β-Oxidation of polyunsaturated fattyacids. Biochem Soc Trans 1988;16:420.Reddy JK, Mannaerts GP: Peroxisomal lipid metabolism. AnnuRev Nutr 1994;14:343.Scriver CR et al (editors): The Metabolic and Molecular Bases of InheritedDisease, 8th ed. McGraw-Hill, 2001.Treem WR et al: Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology1994;19:339.Wood PA: Defects in mitochondrial beta-oxidation of fatty acids.Curr Opin Lipidol 1999;10:107.