3-hydroxy-3-methylglutaryl-CoA reductase messenger RNA (HMGCR mRNA) (HMGCR mRNA)

3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) mRNA is the messenger RNA transcript that encodes the rate-limiting enzyme in the mevalonate pathway, which is essential for the de novo synthesis of cholesterol in the liver (UniProt P04035). While the HMGCR protein is the primary target of statins, the mRNA has become a target for antisense oligonucleotides (ASOs) designed to reduce enzyme expression at the pre-translational level (PubMed: 35413218). By promoting the degradation of HMGCR mRNA, these therapies decrease the synthesis of the HMGCR protein, leading to a reduction in hepatic cholesterol content and a compensatory increase in low-density lipoprotein (LDL) receptor expression. This process enhances the clearance of LDL cholesterol from the plasma, making it a potent strategy for managing dyslipidemia and reducing cardiovascular risk (PubMed: 35413218). Drugs such as AZD8233 (ION-449) have been investigated in clinical trials for their ability to significantly lower LDL-C levels in patients with hypercholesterolemia (NCT04859699). This approach offers a distinct mechanism from traditional enzyme inhibition, potentially providing a more durable or effective reduction in cholesterol for high-risk patients. Targeting the mRNA allows for a more direct reduction in protein expression compared to competitive inhibition of the enzyme's active site. Overall, HMGCR mRNA represents a validated and promising target for the treatment of dyslipidemia and the prevention of atherosclerotic cardiovascular disease.

Other names

HMG-CoA reductase mRNAHMGCR transcript3-hydroxy-3-methylglutaryl-CoA reductase transcript

Antisense oligonucleotide-mediated degradation of mRNA via RNase H1, leading to reduced translation of the HMG-CoA reductase enzyme (PubMed: 35413218).