21.4 Lipid Metabolism

Fatty Acid Synthesis

Fatty acid synthesis occurs in the cytosol, primarily in liver, adipose, and lactating mammary gland. The committed step is acetyl-CoA carboxylase (ACC), which converts acetyl-CoA to malonyl-CoA using ATP and bicarbonate; biotin is the required cofactor. ACC is activated by insulin (dephosphorylation) and citrate; inhibited by glucagon/epinephrine (phosphorylation via AMPK) and palmitoyl-CoA (product feedback). The synthetic enzyme complex is fatty acid synthase (FAS), a homodimeric multifunctional enzyme that iteratively adds two-carbon units (from malonyl-CoA) to a growing chain on an acyl carrier protein (ACP), using NADPH from the pentose phosphate pathway. Each cycle of condensation, reduction, dehydration, and reduction extends the chain by 2 carbons; the final product is palmitate (16:0), requiring 8 acetyl-CoA, 7 ATP, and 14 NADPH. Mitochondrial acetyl-CoA is transported to the cytosol via the citrate shuttle: citrate (from acetyl-CoA + oxaloacetate) crosses the mitochondrial membrane, then ATP-citrate lyase regenerates acetyl-CoA in the cytosol; the cycle returns oxaloacetate as pyruvate via malate, also generating NADPH.

Fatty Acid Oxidation (β-Oxidation)

β-oxidation in the mitochondrial matrix shortens fatty acyl-CoA by two-carbon units, producing acetyl-CoA, NADH, and FADH2. Long-chain fatty acids require the carnitine shuttle to cross the inner mitochondrial membrane: CPT-I (carnitine palmitoyltransferase I, on the outer membrane, inhibited by malonyl-CoA) forms acylcarnitine; translocase moves it across; CPT-II regenerates acyl-CoA in the matrix. Each β-oxidation cycle has four steps — dehydrogenation (acyl-CoA dehydrogenase, FADH2), hydration, dehydrogenation (NADH), thiolysis — releasing acetyl-CoA. Palmitate (16:0) yields 8 acetyl-CoA, 7 FADH2, 7 NADH → ~106 ATP after accounting for the 2 ATP cost of activation. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the most common inborn error of β-oxidation, causes fasting hypoketotic hypoglycemia and can be fatal; expanded newborn screening detects it.

Peroxisomal β-oxidation handles very-long-chain fatty acids (>20 C) that cannot enter mitochondria; it produces H2O2, degraded by catalase, and shortens the chains for mitochondrial completion. α-oxidation in peroxisomes handles branched-chain fatty acids like phytanic acid; ω-oxidation in the ER is a minor pathway upregulated when β-oxidation is impaired.

Ketone Body Metabolism

During fasting, the liver converts acetyl-CoA from β-oxidation into ketone bodies — acetoacetate, β-hydroxybutyrate, and acetone — for export to extrahepatic tissues (brain, heart, muscle). The pathway: 2 acetyl-CoA → acetoacetyl-CoA → HMG-CoA (β-hydroxy-β-methylglutaryl-CoA) → acetoacetate (via HMG-CoA lyase) → β-hydroxybutyrate (via β-hydroxybutyrate dehydrogenase, NADH). The brain cannot use fatty acids but adapts to ketones after several days of fasting. HMG-CoA synthase (mitochondrial, ketogenesis) is distinct from the cytosolic HMG-CoA synthase of cholesterol synthesis. In diabetic ketoacidosis, insulin deficiency and glucagon excess drive uncontrolled ketogenesis; β-hydroxybutyrate predominates, and anion-gap metabolic acidosis ensues.

Cholesterol Synthesis

Cholesterol is synthesized from acetyl-CoA in the cytosol/ER of virtually all cells, with liver being dominant. The committed, rate-limiting step is HMG-CoA reductase, converting HMG-CoA to mevalonate using 2 NADPH. Statins competitively inhibit HMG-CoA reductase. Insulin activates (dephosphorylation); glucagon/AMPK inhibit (phosphorylation). Downstream products include bile acids (the major cholesterol excretion route), steroid hormones, and vitamin D. ACAT (acyl-CoA:cholesterol acyltransferase) esterifies intracellular cholesterol, and CETP (cholesterol ester transfer protein) exchanges cholesteryl esters between lipoproteins.

Phospholipids, Eicosanoids, and Lipoproteins

Phospholipids are synthesized on the ER membrane from diacylglycerol plus a polar head group (choline, ethanolamine, serine, inositol). Phosphatidylcholine (lecithin) and phosphatidylethanolamine are the most abundant. Sphingolipids derive from serine + palmitoyl-CoA → sphingosine; ceramide, sphingomyelin, and glycosphingolipids (gangliosides, cerebrosides) follow. Sphingolipid storage disorders (Tay-Sachs, Gaucher, Niemann-Pick) result from lysosomal catabolic defects.

Eicosanoids — prostaglandins, thromboxanes, leukotrienes — are 20-carbon signaling lipids derived from arachidonic acid (released from membrane phospholipids by phospholipase A2). The cyclooxygenase (COX) pathway produces prostaglandins (vasodilation, pain, fever) and thromboxane A2 (platelet aggregation, vasoconstriction); the lipoxygenase pathway produces leukotrienes (bronchoconstriction, inflammation in asthma). Aspirin irreversibly acetylates COX-1 and COX-2; NSAIDs compete reversibly. Leukotriene receptor antagonists (montelukast) treat asthma.

Lipoproteins transport lipids in plasma. Chylomicrons carry dietary triglycerides from intestine via lymph; VLDL carries endogenous triglycerides from liver; LDL delivers cholesterol to tissues (high LDL → atherogenic); HDL mediates reverse cholesterol transport from peripheral tissues to liver. Apoproteins serve as ligands and enzyme cofactors: ApoB-100 (LDL, VLDL), ApoB-48 (chylomicrons), ApoA-I (HDL), ApoC-II (lipoprotein lipase cofactor), ApoE (chylomicron remnant uptake). Lipoprotein lipase (LPL) on capillary endothelium hydrolyzes chylomicron and VLDL triglycerides. The PA-CAT Bulletin of Information, rev. 20240815, includes Lipid Metabolism within the Biochemistry blueprint; the reciprocal hormonal regulation of lipid synthesis and oxidation is a frequent exam tie.