Describe the biosynthesis and regulation of cholesterol. Give its functions, transport and fate. Add a note on hypercholesterolaemia.

Introduction

Functions

• Membrane structure — modulates fluidity; a major constituent of myelin
• Precursor of bile acids — the largest single use
• Precursor of steroid hormones — cortisol, aldosterone, testosterone, oestrogen
• Precursor of vitamin D, via 7-dehydrocholesterol in skin
• Forms lipid rafts for cell signalling

Biosynthesis

• Site — cytosol and endoplasmic reticulum; requires NADPH and ATP
• All 27 carbons come from acetyl-CoA

2 Acetyl-CoA → Acetoacetyl-CoA → + Acetyl-CoA → HMG-CoA (HMG-CoA synthase, cytosolic) → HMG-CoA reductase — needs 2 NADPH; rate-limiting → mevalonate → Isopentenyl pyrophosphate (5C) → Squalene (30C) → Lanosterol → cholesterol (27C)

Regulation of Hmg-coa Reductase

Transport and Fate

• Carried in plasma as lipoproteins; about 70% is esterified with fatty acid
• LCAT esterifies cholesterol in plasma (on HDL); ACAT does so within cells
• Excretion is only through bile — as bile acids or as free cholesterol. Cholesterol cannot be degraded for energy — its ring structure cannot be broken down by human enzymes

Cholesterol → 7α-hydroxylase — rate-limiting for bile acids → Primary bile acids — cholic and chenodeoxycholic → Conjugated with glycine or taurine → Secreted in bile → 95% reabsorbed in terminal ileum (enterohepatic circulation)

Factors Affecting Plasma Cholesterol

Cholesterol Balance in the Body

• Synthesis falls when dietary intake rises — feedback inhibition of HMG-CoA reductase. This is why dietary cholesterol alone has a modest effect on plasma levels, and why saturated fat matters more than dietary cholesterol
• Bile acid sequestrants (cholestyramine) break the enterohepatic circulation → the liver must make more bile acids from cholesterol → LDL receptors are up-regulated

Applied Aspects

• Atherosclerosis — LDL is oxidised in the intimal wall, taken up by macrophages through scavenger receptors to form foam cells, and the plaque grows. Oxidised LDL is the key step
• Familial hypercholesterolaemia — defective LDL receptor; autosomal dominant; tendon xanthomas, corneal arcus, and premature coronary disease. Homozygotes may have infarction in childhood
• Statins lower LDL both by inhibiting synthesis and by up-regulating LDL receptors — the second effect matters more
• Gallstones form when bile is supersaturated with cholesterol relative to bile salts and lecithin
• Smith–Lemli–Opitz syndrome — a defect in the final step of cholesterol synthesis, causing severe malformations; it shows that cholesterol is essential for normal development
• Statin myopathy — from reduced coenzyme Q synthesis, which shares the mevalonate pathway; ranges from myalgia to rhabdomyolysis
• Cholesterol is not an energy source — unlike fatty acids it yields no ATP, which is why excess can only be excreted or deposited
• Xanthelasma and corneal arcus before the age of 45 should prompt a lipid profile
• Plant sterols compete with cholesterol for intestinal absorption and lower LDL by about 10%
• Cholesterol synthesis needs 18 acetyl-CoA, 36 ATP and 16 NADPH per molecule — a costly pathway
• Nephrotic syndrome raises cholesterol because hypoalbuminaemia stimulates hepatic lipoprotein synthesis
• Hypothyroidism raises LDL by reducing LDL receptor expression — always check thyroid function in unexplained hypercholesterolaemia