De novo cholesterol biosynthesis — ~30 enzymatic steps from acetyl-CoA via the mevalonate pathway. HMG-CoA reductase (HMGCR) is rate-limiting and is the statin target. Diurnal regulation peaks at night, which is why short-half-life statins (simvastatin, fluvastatin) are dosed at bedtime. Sterol-regulatory binding (SREBP-2) downregulates HMGCR when intracellular cholesterol rises — the homeostatic loop statins exploit (cells respond to drug-lowered cholesterol by upregulating LDL-R, which is the actual therapeutic mechanism).
Organ Systems
cardiovascular
digestive
endocrine
Pathway Steps
acetyl-coa → hmg-coa — via HMG-CoA synthase. Two acetyl-CoA condense to acetoacetyl-CoA, then a third yields HMG-CoA. The cytosolic HMG-CoA synthase here feeds sterol synthesis — distinct from the mitochondrial isoform that initiates ketogenesis from the same intermediate.
hmg-coa → mevalonate — via HMG-CoA reductase (HMGCR) — rate-limiting; SREBP-2 regulated; STATIN TARGET. HMG-CoA reductase is the rate-limiting, committed step and the statin target. Sterols feedback-regulate it via SREBP-2/SCAP/INSIG (transcription + ER retention) and accelerated degradation; statins lower LDL largely by de-repressing hepatic LDL receptors.
mevalonate → squalene — via multi-step mevalonate pathway (kinase + decarboxylase + farnesyl-PP synthase + squalene synthase). Mevalonate is phosphorylated and decarboxylated to isopentenyl-PP, the isoprenoid building block. Beyond sterols this branch also makes farnesyl/geranylgeranyl groups (protein prenylation), ubiquinone (CoQ10), dolichol and heme-A — why statins can modestly lower CoQ10.
squalene → cholesterol — via squalene epoxidase → lanosterol → cholesterol (multi-step). Squalene epoxidase (a second regulated, oxygen-dependent step; the analogous fungal enzyme is the terbinafine target) feeds cyclization to lanosterol, then ~19 further steps to cholesterol. The oxygen demand makes late cholesterol synthesis sensitive to hypoxia.
Known Modulators
atorvastatin (inhibitor) — HMG-CoA reductase. Highest LDL-lowering at standard doses (40-80 mg).
rosuvastatin (inhibitor) — HMG-CoA reductase. Most potent statin per mg.