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.
Organ Systems
cardiovascular
digestive
Pathway Steps
intestinal lumen cholesterol → enterocyte cholesterol — via NPC1L1 (Niemann-Pick C1-Like 1) — EZETIMIBE TARGET; ~50% absorption reduction. Dietary and biliary cholesterol is taken up from the intestinal lumen into enterocytes by the transporter NPC1L1 — the rate-limiting absorption step and the target of ezetimibe. The IMPROVE-IT trial showed that adding ezetimibe to a statin further lowers LDL and cuts cardiovascular events.
enterocyte plant sterols → lumen plant sterols — via ABCG5/G8 efflux — prevents phytosterol accumulation. Enterocytes discriminate against plant sterols: the ABCG5/ABCG8 heterodimer pumps absorbed phytosterols (and excess cholesterol) back into the lumen, so almost none enters the body. Loss-of-function mutations cause sitosterolemia, with sterol accumulation and premature atherosclerosis.
macrophage free cholesterol → nascent HDL (apoA-I particle) — via ABCA1 efflux — primary atheroprotective step. Reverse cholesterol transport begins when lipid-laden macrophages efflux free cholesterol to lipid-poor apoA-I via ABCA1, forming nascent (discoidal) HDL. This is the key anti-atherogenic step — unloading arterial foam cells; ABCA1 loss causes Tangier disease with near-absent HDL.
macrophage cholesterol → mature HDL particle — via ABCG1 efflux to spherical HDL. Macrophages also efflux cholesterol to larger, mature HDL particles through the transporter ABCG1, complementing the ABCA1 route. Together they unload the cholesterol that would otherwise build up in the artery wall — the basis of HDL’s protective “efflux capacity”, which tracks risk better than HDL level.
HDL-free cholesterol → HDL-cholesteryl ester — via LCAT (lecithin-cholesterol acyltransferase) — HDL maturation. On the HDL particle, the enzyme LCAT esterifies free cholesterol to cholesteryl ester. Being hydrophobic, the ester moves into the particle core, maturing discoidal HDL into spherical HDL and keeping the surface gradient favorable for continued efflux — a “cholesterol sink” mechanism.
HDL cholesteryl ester → LDL/VLDL cholesteryl ester — via CETP (cholesteryl ester transfer protein) — CETP inhibitor target. Cholesteryl-ester transfer protein (CETP) swaps HDL cholesteryl ester for triglyceride from apoB lipoproteins (LDL/VLDL), redistributing cholesterol away from HDL. This is why CETP inhibitors raise HDL — yet most failed to cut events, clarifying that LDL lowering, not HDL raising, drives benefit.
HDL → hepatocyte cholesterol pool — via SR-BI (scavenger receptor B1) — selective uptake. HDL delivers its cholesterol to the liver largely via the scavenger receptor SR-BI, which selectively extracts cholesteryl ester without degrading the whole particle. This completes reverse cholesterol transport — returning peripheral cholesterol to the one organ able to excrete it.
hepatocyte cholesterol → biliary cholesterol — via ABCG5/G8 + bile acid synthesis (CYP7A1) → intestinal excretion. Hepatocytes excrete cholesterol into bile (again via ABCG5/G8), directly or after conversion to bile acids — the body’s only quantitatively important route for eliminating cholesterol. Biliary secretion is the final common exit of reverse cholesterol transport.
intestinal bile acids → bile acid-sequestrant complex (excreted) — via cholestyramine / colesevelam — interrupts enterohepatic recycling. Most bile acids are reabsorbed (enterohepatic circulation), but bile-acid sequestrants bind them in the lumen to force fecal excretion. The liver then consumes cholesterol to replace the lost bile acids, lowering LDL — the mechanism of resins like cholestyramine.