# Cholesterol > Cholesterol for FMGE Biochemistry: HMG-CoA reductase, statins, bile acids and enterohepatic circulation, familial hypercholesterolaemia and reverse transport. - Canonical URL: https://prepelephant.com/topics/fmge/biochemistry/cholesterol-fmge - Exam / course: FMGE · Subject: Biochemistry - Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team - First published: 2026-10-02 - Last updated: 2026-10-02 - How to cite: "Cholesterol", PrepElephant, https://prepelephant.com/topics/fmge/biochemistry/cholesterol-fmge ## Direct answer Every one of cholesterol's 27 carbons derives from acetyl-CoA, and the committed, rate-limiting step — reduction of HMG-CoA to mevalonate by HMG-CoA reductase in the endoplasmic reticulum — is where statins act as competitive inhibitors. Cholesterol is the precursor of bile acids (rate-limiting enzyme cholesterol 7α-hydroxylase), of steroid hormones, and of vitamin D via 7-dehydrocholesterol in sunlit skin. Clearance depends on the hepatic LDL receptor, which the protein PCSK9 marks for degradation — the target of PCSK9 inhibitors — and on HDL-mediated reverse transport, in which LCAT esterifies cholesterol in plasma and CETP swaps those esters for triglyceride. ## What you must remember - HMG-CoA reductase is rate-limiting, competitively inhibited by statins and feedback-inhibited by cholesterol; short-acting statins are dosed at night because the enzyme's activity peaks then. - Bile acid synthesis: cholesterol 7α-hydroxylase makes the primary bile acids, cholic and chenodeoxycholic, which are conjugated with glycine or taurine; gut bacteria convert them to the secondary acids deoxycholic and lithocholic. - The enterohepatic circulation reabsorbs about 95% of bile salts in the terminal ileum — exploited by sequestrants such as cholestyramine and by ezetimibe, which blocks the intestinal transporter NPC1L1; ileal resection or Crohn disease causes bile salt loss, steatorrhoea and gallstones. - Familial hypercholesterolaemia: an autosomal dominant LDL receptor (or apoB-100) defect with tendon xanthomas, corneal arcus before 45 years, xanthelasma and premature coronary disease; homozygotes grow planar cutaneous xanthomas in childhood and may need LDL apheresis or transplantation-level therapy. - Reverse transport: HDL's apoA-I activates LCAT, which esterifies free cholesterol within the particle; CETP exchanges those cholesteryl esters for triglycerides with VLDL and LDL; Tangier disease (ABC A1 defect) shows near-absent HDL, orange tonsils and hypocholesterolaemia. - Plasma cholesterol travels mostly esterified (about 70%) by LCAT action — the free-to-esterified ratio is a sensitive index of liver synthetic function in advanced disease. - Bile salt sequestrants lower LDL but raise triglycerides; niacin uniquely lowers LDL and triglycerides while raising HDL, with flushing attenuated by aspirin. ## A worked case: infarction at twenty-eight A 28-year-old gym trainer survives an anterior myocardial infarction; total cholesterol is 340 mg/dL with LDL 250, triglycerides normal, and both parents carry stents placed in their forties. Examination reveals thickened Achilles tendons — tendon xanthomas — and an arcus before age 45. Reason it through: secondary causes (hypothyroidism, nephrotic syndrome, diabetes, cholestasis) are excluded with TSH, urine protein and liver tests; the tendon xanthomas with a dominant family history and an LDL this high are close to pathognomonic of heterozygous familial hypercholesterolaemia, found in roughly one in 250 people in many populations. Management is high-intensity statin (up-titrated to the maximum tolerated dose, since receptor numbers are halved and every point of LDL lowering matters), ezetimibe added for the additional 15–20% reduction, and a PCSK9 inhibitor when targets are missed. The homozygous contrast is the viva favourite: LDL above 500 mg/dL, childhood cutaneous xanthomas, supravalvular aortic stenosis and infarction in the first two decades. Cascade screening of the family converts one index case into a preventable-disease pedigree — an exam answer that is also good medicine. ## Where students slip LCAT (plasma, HDL-associated) is confused with ACAT (intracellular, esterifying cholesterol for storage), and CETP's name is remembered without its trade — cholesteryl esters out of HDL, triglycerides in. Second, xanthelasma is treated as proof of hypercholesterolaemia when it can occur with normal lipids, whereas a tendon xanthoma almost always means familial hypercholesterolaemia. Third, ezetimibe's target (NPC1L1) is stated as the LDL receptor or even a statin-potentiator; it is an intestinal cholesterol transporter blocker, hence complementary to statins. Fourth, PCSK9 logic runs backwards under stress: more PCSK9 means fewer LDL receptors and higher LDL, so inhibiting PCSK9 lowers LDL. Fifth, 7-dehydrocholesterol is the skin intermediate of vitamin D, not a bile acid precursor; keeping the two 7-enzymes straight (7α-hydroxylase for bile, 7-dehydrocholesterol for vitamin D) settles several stems. Finally, forgetting that sequestrants raise triglycerides leads to their wrong use in hypertriglyceridaemia. ## Frequently asked questions ### Which enzyme is rate-limiting in cholesterol synthesis and in bile acid synthesis? HMG-CoA reductase for cholesterol synthesis; cholesterol 7α-hydroxylase for the conversion to bile acids — both inhibited by their end products. ### How does ezetimibe lower LDL? It blocks NPC1L1, the intestinal cholesterol transporter at the brush border, cutting sterol absorption so that LDL receptors clear more cholesterol from plasma. ### Which disease shows orange tonsils and near-absent HDL? Tangier disease, an ABC A1 transporter defect that prevents lipidation of apoA-I, so HDL is rapidly degraded. ### How much of the bile salt pool is reabsorbed, and where? About 95% in the terminal ileum, by active sodium-coupled transport — the reason ileal disease causes gallstones and steatorrhoea. ### Which enzyme esterifies cholesterol in plasma? LCAT, activated by apoA-I on HDL; about 70% of plasma cholesterol circulates esterified. ### What genetic and inheritance pattern defines familial hypercholesterolaemia? Mostly LDL receptor defects inherited autosomal dominantly, with xanthomas and premature coronary disease; homozygous disease presents in childhood.