Chapter 16: Lipid Metabolism

Fatty acid synthesis occurs in the cytosol through iterative two-carbon unit additions, beginning with acetyl-CoA carboxylase converting acetyl CoA to malonyl CoA, followed by a four-step elongation cycle catalyzed by fatty acid synthase in eukaryotes. Beyond the initial sixteen to eighteen carbon backbone, specialized elongases and desaturases extend chains and introduce double bonds, though mammals cannot synthesize certain polyunsaturated fatty acids and must obtain them dietarily. Complex lipids including triacylglycerols and phospholipids derive from the common intermediate phosphatidate, while sphingolipids form through serine and palmitoyl CoA condensation to generate ceramide as a central precursor. Eicosanoids, signaling molecules synthesized from arachidonate, include prostaglandins and leukotrienes with important regulatory roles. Cholesterol biosynthesis, proceeding from acetyl CoA through the mevalonate pathway, is primarily regulated by HMG-CoA reductase, the target of statin medications. Fatty acid degradation through beta-oxidation breaks down fatty acids into acetyl CoA units via sequential four-step cycles, utilizing the carnitine shuttle system for mitochondrial entry. During fasting, excess acetyl CoA from fatty acid oxidation is converted into ketone bodies, which serve as alternative fuels for the brain and muscles. Lipids, being hydrophobic, require specialized transport mechanisms through lipoproteins such as chylomicrons, VLDL, LDL, and HDL, each serving distinct roles in lipid distribution and cholesterol homeostasis. Hormonal regulation coordinates lipid metabolism with energy needs through insulin signaling during fed states, which promotes synthesis and storage, and glucagon or epinephrine signaling during fasting, which mobilizes stored fatty acids for oxidation.