Cholesterol is synthesized from acetyl-CoA in the cytoplasm of every cell (especially in the liver). The pathway consumes 18 acetyl-CoA, 18 NADPH, and 36 ATP to build one cholesterol molecule - an enormous investment.
Cholesterol: one intermediate, two destinations
Pathway map
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Scroll sideways to see the whole map.
HMG-CoA reductase: the regulated step Mitochondrion: ketone bodies Cytosol and ER: cholesterol Acetyl-CoA
The same intermediate, two destinationsHMG-CoA is made in both compartments. In the mitochondrion, HMG-CoA lyase cleaves it to acetoacetate and you get ketone bodies. In the cytosol, HMG-CoA reductase reduces it to mevalonate and you get cholesterol. Same molecule, different address, opposite outcome.
Why statins work where they doHMG-CoA reductase is the rate-limiting step and sits in the ER membrane. Statins are competitive inhibitors of it, so the liver makes less cholesterol, compensates by putting more LDL receptors on its surface, and pulls LDL out of the blood. The receptor response, not the synthesis block, is what lowers blood LDL.
Good and bad cholesterolThe cholesterol is identical; only the direction differs. LDL carries it out to tissues and deposits it in artery walls when it is oxidized. HDL runs reverse transport, collecting cholesterol from tissues and returning it to the liver for disposal as bile acids.
Cholesterol is not just a villain: it is the backbone of every steroid hormone, bile acid, and vitamin D, and it is what keeps a membrane from freezing or melting. The body makes far more of it than most diets supply, which is why blocking synthesis lowers blood levels more effectively than eating less of it.
Notice the raw material: acetyl-CoA - the same molecule that feeds the TCA cycle. Cholesterol synthesis is one of several anabolic pathways that COMPETE with the TCA cycle for acetyl-CoA. When the cell has excess acetyl-CoA and plenty of ATP (fed state), acetyl-CoA gets diverted into biosynthesis: cholesterol, fatty acids, and ketones. When ATP is low (fasting), acetyl-CoA is pushed through the TCA cycle → ETC → ATP. The ATP/ADP and NADH/NAD+ ratios dictate which direction acetyl-CoA flows.
Statin drugs (atorvastatin, simvastatin, etc.) are competitive inhibitors.
HMG-CoA Is a Branch Point
HMG-CoA is produced in the cytoplasm for cholesterol synthesis and in liver mitochondria for ketogenesis. Two separate HMG-CoA pools, two separate fates:
What is the rate-limiting enzyme of cholesterol biosynthesis, and what drug class inhibits it?
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HMG-CoA reductase, which catalyzes HMG-CoA → mevalonate (using 2 NADPH). Statins (atorvastatin, simvastatin, lovastatin, etc.) are competitive inhibitors. By blocking this enzyme in the liver, statins reduce cholesterol synthesis, upregulate LDL receptors, and lower blood LDL.
HMG-CoA can go to either cholesterol or ketone bodies. What determines the fate?
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Compartment. Cytoplasmic HMG-CoA (from cytosolic acetyl-CoA) goes to cholesterol via HMG-CoA reductase. Mitochondrial HMG-CoA (from acetyl-CoA generated by beta-oxidation) goes to acetoacetate (ketone body) via HMG-CoA lyase - only in the liver. The separation of pools prevents crosstalk.
Why does statin therapy lower blood LDL cholesterol?
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Statins inhibit hepatic HMG-CoA reductase, reducing cholesterol synthesis in the liver. To maintain its cholesterol supply, the liver upregulates LDL receptors on its surface, importing more LDL from blood. The result: lower circulating LDL and reduced cardiovascular risk. The effect is indirect (via LDL receptor upregulation) rather than direct inhibition of LDL production.
