Familial hypercholesterolaemia (FH) is most commonly caused by mutations in the LDL receptor gene. How does LDL receptor deficiency cause elevated circulating LDL?
- A Increased LDL synthesis from VLDL due to upregulated apoB-100 production
- B Increased lipolysis of adipose tissue releases fatty acids that hepatocytes convert to more LDL
- C Reduced hepatic clearance of LDL — IDL accumulates and is converted to more LDL, while LDL itself is not taken up and catabolised via receptor-mediated endocytosis ✓
- D Defective PCSK9 degradation of LDL receptors is the primary mechanism
Explanation
LDL receptors on hepatocytes normally bind and internalise apoB-100-containing particles (IDL and LDL) via receptor-mediated endocytosis (coated pits → endosomes → lysosomes). In FH, reduced functional LDL receptors prolong IDL half-life, leading to more IDL→LDL conversion by hepatic lipase, and then LDL also cannot be cleared. Both effects raise plasma LDL. Intracellularly, absent cholesterol delivery means SREBP-2 is not suppressed, further upregulating HMG-CoA reductase and LDL receptor genes — but the receptor cannot function. Statins work by increasing LDL receptor expression in FH heterozygotes. PCSK9 normally degrades LDL receptors; PCSK9 inhibitors increase receptor numbers — the reverse of FH.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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