Chapter 30: Oxidation of Fatty Acids and Ketone Bodies

Fatty acid mobilization from adipose tissue triacylglycerols is triggered by low insulin levels and elevated counterregulatory hormones including glucagon and epinephrine, which activate hormone-sensitive lipase. Free fatty acids enter circulation bound to albumin and are transported to tissues where they undergo activation to acyl-CoA derivatives. The carnitine shuttle system, comprising carnitine palmitoyltransferase I, II, and the inner membrane translocase, facilitates translocation of long-chain acyl groups across the mitochondrial membrane into the matrix where oxidative catabolism proceeds. Beta-oxidation sequentially cleaves two-carbon units as acetyl-CoA while generating reducing equivalents in the form of NADH and FADH2 that feed into oxidative phosphorylation, yielding approximately 106 ATP molecules per palmitate molecule. Specialized pathways handle structural variants: unsaturated fatty acids require isomerase and reductase enzymes to rearrange double bonds, odd-chain substrates produce propionyl-CoA units that are converted to succinyl-CoA through vitamin B12-dependent reactions, and medium-chain fatty acids bypass carnitine transport for direct oxidation. Very-long-chain and branched-chain fatty acids undergo initial oxidation in peroxisomes via alpha-oxidation and shortened chain beta-oxidation, while microsomal omega-oxidation produces dicarboxylic acid intermediates. Acetyl-CoA derived from fatty acid catabolism enters either the tricarboxylic acid cycle for complete oxidation or hepatic ketone body synthesis. The liver synthesizes acetoacetate and beta-hydroxybutyrate, which serve as alternative fuels for extrahepatic tissues including muscle, kidney, intestine, and brain during extended fasting periods. The chapter integrates clinical disorders illustrating disrupted fatty acid metabolism: medium-chain acyl-CoA dehydrogenase deficiency causing hypoketotic hypoglycemia, carnitine palmitoyltransferase II deficiency presenting with exercise-induced myopathy, Zellweger syndrome from peroxisomal biogenesis defects, and Refsum disease from alpha-oxidation impairment. Diabetic ketoacidosis represents pathological ketosis with severe hyperglycemia and metabolic acidosis. Hormonal control mechanisms including AMP-activated protein kinase regulation of malonyl-CoA and carnitine palmitoyltransferase I modulation ensure appropriate substrate availability and utilization while sparing glucose and preserving protein during prolonged energy restriction.