Cholesterol
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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.