Chapter 22: Fatty Acid Metabolism

Once transported to target tissues via albumin, fatty acids are activated to acyl CoA and shuttled into the mitochondrial matrix by the carnitine transport system, a critical regulatory step involving carnitine acyltransferase I and II. The core of degradation is the beta-oxidation pathway, a recurring four-step sequence—oxidation by FAD, hydration, oxidation by NAD+, and thiolysis by coenzyme A—that shortens the fatty acid chain by two carbons per cycle, generating FADH2, NADH, and acetyl CoA for ATP production via the citric acid cycle and oxidative phosphorylation. The chapter expands on the specific enzymatic requirements for oxidizing unsaturated fatty acids, which necessitate isomerases and reductases, and odd-chain fatty acids, which yield propionyl CoA and require vitamin B12 (cobalamin) for conversion to succinyl CoA. Special attention is given to peroxisomal oxidation for very long-chain fatty acids and the formation of ketone bodies (acetoacetate, D-3-hydroxybutyrate, and acetone) in the liver during starvation or diabetes, serving as alternative fuels for the brain. In contrast, fatty acid synthesis occurs in the cytoplasm, utilizing NADPH and precursors transported from mitochondria as citrate. The process acts as a chemical reverse of degradation but employs a distinct enzymatic complex called Fatty Acid Synthase and an Acyl Carrier Protein (ACP) to construct palmitate from acetyl CoA and malonyl CoA. Regulation is tightly controlled at the committed step catalyzed by acetyl CoA carboxylase, which is modulated by phosphorylation (AMP-activated protein kinase), allosteric effectors (citrate, palmitoyl CoA), and hormonal signals (insulin stimulating synthesis, glucagon inhibiting it). Finally, the text covers the elongation and desaturation of fatty acids in the endoplasmic reticulum to produce essential fatty acids and signaling molecules known as eicosanoids, including prostaglandins and leukotrienes derived from arachidonate.