Category: transport
Distinct from cholesterol_synthesis (mevalonate / HMG-CoA reductase / SREBP biology). This pathway covers the **whole-body cholesterol balance** arm — intestinal absorption + bile-acid recycling + macrophage cholesterol efflux + HDL reverse cholesterol transport. Step 1: intestinal cholesterol absorption — NPC1L1 (Niemann-Pick C1-Like 1) at the enterocyte brush border imports cholesterol + plant sterols; ezetimibe binds NPC1L1 → ~50% reduction in cholesterol absorption (key Rx, additive to statins per IMPROVE-IT). Step 2: enterocyte ABCG5/G8 effluxes plant sterols back into the lumen (humans are intolerant of phytosterol accumulation — gain-of-function loss causes sitosterolemia). Step 3: hepatic LDL-R clears LDL from plasma; PCSK9 binds LDL-R → lysosomal degradation (covered in ldl_receptor_pcsk9_axis). Step 4: macrophage cholesterol efflux — ABCA1 transports free cholesterol + phospholipids to apoA-I → nascent HDL; ABCG1 transfers cholesterol to mature HDL. Step 5: HDL maturation — LCAT esterifies free cholesterol → cholesteryl ester; CETP transfers CE from HDL to LDL/VLDL (CETP inhibitors anacetrapib + obicetrapib raise HDL). Step 6: hepatic cholesterol uptake from HDL via SR-BI; biliary excretion via ABCG5/G8 → bile + intestinal lumen (the "reverse cholesterol transport" loop). Step 7: bile acid sequestrants (cholestyramine, colesevelam) bind bile acids in the gut → prevent reabsorption → liver compensates by upregulating LDL-R + cholesterol → bile acid conversion → ↓ plasma LDL-C. Step 8: niacin (>1-3g/day) modestly raises HDL + lowers Lp(a) — mechanism via adipocyte HM74A (niacin receptor) and hepatic effects; flushing limits tolerability. Cross-links: [[cholesterol_synthesis]], [[ldl_receptor_pcsk9_axis]], [[bile_acid_synthesis]].