Classify the plasma lipoproteins. Describe their metabolism and the role of apolipoproteins. Add a note on the hyperlipoproteinaemias.

Definition and Structure

• Core — non-polar lipids: triglyceride and cholesteryl ester
• Surface — amphipathic: phospholipid, free cholesterol and apolipoproteins
• Density is inversely related to lipid content — the more triglyceride, the lower the density

Classification

Important Apolipoproteins

Metabolism

A. Exogenous pathway (dietary fat)

Dietary fat → chylomicron (intestine) → Lymph → blood; acquires apo C-II and E from HDL → Lipoprotein lipase on capillary endothelium hydrolyses TG → Free fatty acids to adipose and muscle → Chylomicron remnant → taken up by liver via apo E

B. Endogenous pathway

Liver → VLDL → Lipoprotein lipase removes TG → IDL → Further TG removal by hepatic lipase → LDL → Taken up by LDL (apo B-100) receptors in liver and tissues

C. Reverse cholesterol transport

Nascent HDL from liver and intestine → Picks up free cholesterol from tissues via ABCA1 → LCAT (activated by apo A-I) esterifies it → Mature HDL → Delivers cholesterol to liver (SR-B1) or transfers to VLDL/LDL via CETP → Excreted in bile

• This is why HDL is protective — it is the only route by which peripheral cholesterol returns to the liver for excretion

Lipoprotein Lipase

• Located on the capillary endothelium of adipose tissue, muscle and lactating breast
• Activated by apo C-II; induced by insulin
• Released into plasma by heparin — "clearing factor"
• The adipose enzyme has a high Km (works after a meal); the muscle enzyme a low Km (works when fat is scarce)

Fredrickson Classification of Hyperlipoproteinaemias

LDL Receptor Pathway (brown and Goldstein)

LDL binds the LDL receptor via apo B-100 → Internalised in clathrin-coated pits → Endosome → lysosome → Cholesteryl ester hydrolysed → free cholesterol → Three consequences

• Inhibits HMG-CoA reductase → less synthesis
• Down-regulates the LDL receptor → less uptake
• Activates ACAT → excess is esterified and stored
• This feedback is absent on the macrophage scavenger receptor, which is why foam cells form

Applied Aspects

• Lipid profile — total cholesterol, triglyceride, HDL, and LDL by the Friedewald formula: LDL = Total − HDL − (TG ÷ 5). Invalid if triglyceride exceeds 400 mg/dL
• Abetalipoproteinaemia — no apo B → no chylomicrons or VLDL → fat malabsorption, acanthocytosis, retinitis pigmentosa, neurological damage from vitamin E deficiency
• Tangier disease — ABCA1 defect → almost no HDL → orange tonsils and neuropathy
• Very high triglyceride (> 1000 mg/dL) causes acute pancreatitis — a medical emergency independent of cardiovascular risk
• Lp(a) resembles plasminogen and is an independent risk factor for thrombosis and atherosclerosis
• Fasting is no longer required for a routine lipid profile in most guidelines, except when triglyceride is very high
• Familial combined hyperlipidaemia (type IIb) is the commonest genetic dyslipidaemia and a frequent finding in premature coronary disease
• Secondary causes must be excluded first — hypothyroidism, nephrotic syndrome, diabetes, alcohol, and drugs such as thiazides and steroids