Acetyl-CoA to mevalonate via HMG-CoA reductase, the rate-limiting step
Expansion
Pathway: acetyl-CoA to HMG-CoA to mevalonate (via HMG-CoA reductase, the rate-limiting step) to squalene to cholesterol. Synthesis occurs mainly in the liver, in the cytoplasm and endoplasmic reticulum.
Regulation
- Inhibited by cholesterol itself, through SREBP transcriptional control and enzyme degradation
- Inhibited by glucagon (phosphorylation), stimulated by insulin
- Diurnal, peaking at night
Uses of cholesterol: membranes, bile acids (the main route of elimination), steroid hormones, and vitamin D.
Statins inhibit HMG-CoA reductase. The fall in intracellular cholesterol upregulates LDL receptors, and this receptor effect rather than reduced synthesis is the main reason LDL falls. It also explains why statins are less effective in homozygous familial hypercholesterolaemia, where receptors are absent.
The same pathway produces isoprenoids and coenzyme Q10, which is one proposed explanation for statin-related myalgia.
Note that HMG-CoA is also an intermediate of ketogenesis, but that occurs in the mitochondrion, kept separate from cytoplasmic cholesterol synthesis.