Lipid Metabolism

Lipids are a structurally diverse group of hydrophobic molecules serving as the primary long-term energy store, structural components of membranes, precursors of hormones and bile acids, and signalling molecules. Understanding lipid metabolism is essential for interpreting cardiovascular risk, metabolic disease, and pharmacological targets including statins and fibrates.

Fatty Acid Oxidation: Beta-Oxidation

Fatty acid oxidation (beta-oxidation) occurs in the mitochondrial matrix. Activation: cytoplasmic fatty acids are esterified to acyl-CoA by acyl-CoA synthetase, consuming 2 ATP equivalents (ATP → AMP + PPi). Transport: long-chain acyl-CoA cannot cross the inner mitochondrial membrane; carnitine palmitoyltransferase I (CPT-I) on the outer mitochondrial membrane transfers the acyl group to carnitine; acylcarnitine crosses via the carnitine-acylcarnitine translocase; CPT-II on the inner membrane regenerates acyl-CoA. CPT-I is the rate-limiting step and is inhibited by malonyl-CoA (the first committed intermediate of fatty acid synthesis), preventing futile simultaneous synthesis and oxidation. The beta-oxidation spiral for a saturated even-chain fatty acid involves four reactions per cycle: (1) FAD-dependent oxidation by acyl-CoA dehydrogenase (→ FADH2), (2) hydration by enoyl-CoA hydratase, (3) NAD+-dependent oxidation by L-3-hydroxyacyl-CoA dehydrogenase (→ NADH), (4) thiolytic cleavage by thiolase, releasing acetyl-CoA and a shortened acyl-CoA. For palmitate (C16:0), seven cycles yield 8 acetyl-CoA, 7 FADH2, and 7 NADH. After subtracting the 2 ATP activation cost, net yield is approximately 106 ATP — reflecting the greater energy density of fats vs. carbohydrates.

Ketogenesis and Ketone Body Utilisation

During prolonged fasting or uncontrolled type 1 diabetes, hepatic acetyl-CoA from beta-oxidation exceeds TCA cycle capacity (oxaloacetate is diverted to gluconeogenesis). Excess acetyl-CoA is converted to ketone bodies exclusively in hepatic mitochondria: two acetyl-CoA → acetoacetyl-CoA (thiolase) → HMG-CoA (HMG-CoA synthase, rate-limiting) → acetoacetate + acetyl-CoA (HMG-CoA lyase). Acetoacetate is reduced to beta-hydroxybutyrate (the major circulating ketone) by beta-hydroxybutyrate dehydrogenase, or spontaneously decarboxylated to acetone (the exhaled component causing "fruity breath"). In extrahepatic tissues (brain, heart, muscle), beta-hydroxybutyrate is reconverted to acetyl-CoA via succinyl-CoA:acetoacetate CoA transferase (thiophorase — absent in liver, preventing futile cycling). The brain adapts to use beta-hydroxybutyrate as its primary fuel during starvation (glucose-sparing). In diabetic ketoacidosis (DKA), unregulated ketogenesis causes life-threatening metabolic acidosis (pH <7.3) with Kussmaul breathing, ketonuria, and dehydration; treatment is insulin infusion plus fluid and electrolyte replacement.

Lipid Synthesis

Fatty acid synthesis occurs in the cytoplasm and requires acetyl-CoA (transported from mitochondria as citrate via the citrate shuttle), NADPH (from the pentose phosphate pathway and malic enzyme), and the enzyme fatty acid synthase (FAS), a large multifunctional complex. Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA — the committed, rate-limiting step — requiring biotin and ATP. Malonyl-CoA is the building block for chain elongation: each cycle adds two carbons and consumes 1 ATP and 2 NADPH. FAS produces palmitate (C16:0) as its primary product. Cholesterol is synthesised via the mevalonate pathway: acetyl-CoA → HMG-CoA → mevalonate (rate-limiting step, catalysed by HMG-CoA reductase) → isopentenyl pyrophosphate → squalene → cholesterol. HMG-CoA reductase is regulated by sterol-mediated SREBP-2 transcriptional repression and by AMPK phosphorylation (inactivating). Statins competitively inhibit HMG-CoA reductase, reducing intracellular cholesterol, upregulating LDL receptor expression, and lowering plasma LDL by 30–60%.

Lipoproteins and Cardiovascular Risk

Lipids are transported in blood as lipoproteins. Chylomicrons (from intestine) carry dietary triglycerides; VLDL (from liver) carries endogenous triglycerides; IDL and LDL are progressively delipidated VLDL, with LDL delivering cholesterol to peripheral tissues via the LDL receptor (apoB-100 mediated). HDL mediates reverse cholesterol transport (periphery → liver), with LCAT esterifying cholesterol on HDL surfaces. Lipoprotein lipase (LPL), activated by apoC-II, hydrolyses triglycerides in chylomicrons and VLDL at capillary endothelium. Elevated LDL promotes atherosclerosis; PCSK9 gain-of-function mutations and LDL receptor loss-of-function mutations (familial hypercholesterolaemia) dramatically elevate LDL and cardiovascular risk.

Clinical Relevance

Diabetic ketoacidosis (DKA) is the classic clinical consequence of uncontrolled ketogenesis. Non-alcoholic fatty liver disease (NAFLD) results from excess hepatic lipid synthesis and impaired export. Familial hypercholesterolaemia (FH) — affecting 1 in 200–500 people in its heterozygous form — causes tendon xanthomata, corneal arcus, and premature atherosclerosis; treatment with high-intensity statins and PCSK9 inhibitors (evolocumab, alirocumab) can normalise LDL and reduce cardiovascular events.