Chem Path 02: Lipids and Lipoproteins

Lipids are hydrophobic molecules essential for cell membrane structure, energy storage, and signalling. Because lipids are insoluble in aqueous plasma, they are transported as lipoproteins — complexes of lipid and apolipoprotein (apoprotein) that provide structural stability and direct the lipoprotein to its target tissue by interacting with cell-surface receptors.

The major plasma lipids are: free fatty acids (bound to albumin), triacylglycerols (TAGs, the primary energy storage lipid), cholesterol (membrane component and steroid hormone precursor), and phospholipids (membrane components and emulsifiers). Lipoproteins are classified by density, reflecting their lipid:protein ratio — the higher the lipid content, the lower the density.

Chylomicrons are the largest lipoproteins, assembled in intestinal enterocytes to transport dietary (exogenous) TAGs and cholesterol from the gut to peripheral tissues. Their key apoprotein is ApoB-48. Lipoprotein lipase (LPL) in capillaries of muscle and adipose tissue hydrolyses chylomicron TAGs, releasing fatty acids for uptake. The chylomicron remnants are taken up by the liver via ApoE binding to LDL receptors.

VLDL (very low-density lipoprotein) is assembled in the liver to transport endogenous TAGs synthesised from excess carbohydrate and fatty acids. Its key apoprotein is ApoB-100. LPL removes TAGs from VLDL, progressively converting it to IDL and then LDL.

LDL (low-density lipoprotein) is the principal cholesterol-carrying lipoprotein (approximately 70% of plasma cholesterol). It delivers cholesterol to cells via the LDL receptor (LDLR), which recognises ApoB-100. After receptor-mediated endocytosis, cholesterol is released and used for membrane synthesis; surplus cholesterol suppresses LDLR expression. Oxidised LDL is taken up by macrophage scavenger receptors in arterial walls, forming foam cells — the basis of atherogenesis. Elevated LDL is the primary modifiable risk factor for atherosclerosis.

HDL (high-density lipoprotein) performs reverse cholesterol transport — removing cholesterol from peripheral tissues (including atherosclerotic plaques) and returning it to the liver for excretion. LCAT (lecithin-cholesterol acyltransferase) esterifies cholesterol on HDL; CETP (cholesteryl ester transfer protein) transfers cholesteryl esters to other lipoproteins. HDL is protective: low HDL is an independent cardiovascular risk factor.

Statins (HMG-CoA reductase inhibitors) block the rate-limiting step in cholesterol biosynthesis, reducing hepatic cholesterol synthesis. This upregulates LDLR expression → increased LDL clearance → reduced plasma LDL. They are first-line pharmacotherapy for hypercholesterolaemia and atherosclerotic cardiovascular disease prevention.

Familial hypercholesterolaemia (FH) is caused by loss-of-function mutations in LDLR (most common), ApoB (ligand), or gain-of-function mutations in PCSK9 (which promotes LDLR degradation); inheritance is autosomal dominant. FH causes markedly elevated LDL and premature atherosclerosis (MI in the third to fourth decade in heterozygotes, childhood in homozygotes). Clinical features include xanthomas (tendon, especially Achilles and extensor tendons of hands) and corneal arcus.

Lp(a) is an LDL-like particle with an additional apoprotein(a) molecule linked to ApoB-100. High Lp(a) is an independent cardiovascular risk factor; Lp(a) levels are largely genetically determined and do not respond to statins.