Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis. (R)-mevalonate + CoA + 2 NADP(+) = (3S)-hydroxy-3-methylglutaryl-CoA + 2 H(+) + 2 NADPH Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3. Homotetramer. Homodimer. By estrogen; in male liver. Belongs to the HMG-CoA reductase family.