Lipid Metabolism

Lipids serve as the body's primary long-term energy reserve. Dietary fats are emulsified by bile salts, digested by lipases, and transported as chylomicrons. Endogenous lipids are synthesized in the liver and transported via VLDL, LDL, and HDL. Triglyceride breakdown (lipolysis) in adipose tissue is stimulated by glucagon and adrenaline, releasing free fatty acids (FFAs). FFAs undergo beta-oxidation in the mitochondrial matrix, producing acetyl-CoA, NADH, and FADH2. Acetyl-CoA then enters the Krebs cycle or, in the liver during fasting, is converted into ketone bodies (acetoacetate and 3-beta-hydroxybutyrate) for use by the brain. Conversely, fatty acid synthesis (lipogenesis) occurs in the cytosol when energy is abundant, using acetyl-CoA and NADPH. Cholesterol synthesis, primarily in the liver, is regulated by HMG-CoA reductase. Dysregulation leads to dyslipidaemias, contributing to atherosclerosis, or conditions like diabetic ketoacidosis (DKA) when ketone production becomes excessive.

Beta-oxidation reduces fatty acids by two carbons at a time. Each cycle produces 1 NADH, 1 FADH2, and 1 Acetyl-CoA. For a 16-carbon palmitate, this yields substantially more ATP than glucose oxidation. The entry of fatty acids into the mitochondria is the rate-limiting step for oxidation, facilitated by Carnitine Palmitoyltransferase I (CPT-I), which is inhibited by Malonyl-CoA (an intermediate of synthesis). Fatty acid synthesis begins with the conversion of acetyl-CoA to malonyl-CoA by Acetyl-CoA carboxylase, requiring Biotin (B7). Pentose Phosphate Pathway provides the necessary NADPH for this. Cholesterol synthesis starts from acetyl-CoA; HMG-CoA reductase converts HMG-CoA to mevalonate. This enzyme is the target of statins. Lipoproteins are classified by density: Chylomicrons (highest TG), VLDL, LDL (highest cholesterol), and HDL (highest protein). Apoproteins like ApoB-100 (on LDL) and ApoA-I (on HDL) are critical for receptor binding and enzyme activation.

Hyperlipidaemia (elevated LDL/TGs) is a major risk factor for cardiovascular disease and is managed with statins and lifestyle changes. Diabetic Ketoacidosis (DKA) occurs in Type 1 Diabetes when a lack of insulin causes uncontrolled lipolysis and ketogenesis, leading to life-threatening acidosis. Carnitine deficiency or CPT-I/II defects can cause non-ketotic hypoglycaemia during fasting. Familial Hypercholesterolaemia (FH) is a genetic defect in the LDL receptor leading to early-onset MI and physical signs like tendon xanthomata or corneal arcus. Acute pancreatitis can be triggered by severe hypertriglyceridaemia (>10 mmol/L).

Key tests: Fasting Lipid Profile (Total Cholesterol, HDL, LDL, Triglycerides), Serum Ketones (monitoring DKA), and Glucose. Genetic testing for FH and specialized tests like ApoB levels or carnitine challenge may be indicated in specific cases. LFTs are usually checked before starting statins.

Hyperlipidaemia is managed with Statins (HMG-CoA reductase inhibitors), Ezetimibe, or PCSK9 inhibitors. DKA management follows a strict protocol of fluid resuscitation, intravenous insulin, and potassium replacement. FH requires lifelong high-intensity statins and screening of first-degree relatives. Pancreatitis from high TGs is managed with fibrates and sometimes plasmapheresis.