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 Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate (By similarity). Phosphorylation at Ser-871 down-regulates the catalytic activity (PubMed:8415689). Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3. Homotetramer. Homodimer. Interacts (via its SSD) with INSIG1; the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway (PubMed:17090658). Interacts with UBIAD1 (By similarity). N-glycosylated. Glycosylated with high mannose chains including Man(6)(GlcNAc)(2), Man(7)(GlcNAc)(2) and Man(8)(GlcNAc)(2) (PubMed:6580634). Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner (By similarity). Undergoes sterol-mediated ubiquitination and ER-associated degradation (ERAD) (PubMed:14563840, PubMed:15247208, PubMed:17090658, PubMed:29374057). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1 or INSIG2 (PubMed:14563840, PubMed:17090658). The INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating ubiquitination of the reductase (PubMed:14563840, PubMed:29374057). The ubiquitinated reductase is then extracted from the ER membrane and delivered to cytosolic 26S proteosomes by a mechanism probably mediated by the ATPase Valosin-containing protein VCP/p97 (PubMed:14563840). The INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, initiating ubiquitination of the reductase (By similarity). Lys-248 is the main site of ubiquitination (PubMed:14563840, PubMed:15247208). Ubiquitination is enhanced by the presence of a geranylgeranylated protein (By similarity). Phosphorylated. Phosphorylation at Ser-871 reduces the catalytic activity. Belongs to the HMG-CoA reductase family.