Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) (HMGCS2)

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) is the rate-limiting enzyme in the ketogenesis pathway, responsible for converting acetyl-CoA and acetoacetyl-CoA into HMG-CoA within the liver (UniProt P54868). This process is vital during fasting or low-carbohydrate intake, as it provides ketone bodies like beta-hydroxybutyrate and acetoacetate to serve as alternative energy sources for the brain, heart, and skeletal muscles (StatPearls, Ketogenesis). Ketogenesis induction is a therapeutic strategy used primarily in the management of refractory pediatric epilepsy through the ketogenic diet and is being explored for neuroprotective effects in Alzheimer’s and Parkinson’s diseases (PubMed PMID: 31665015). Pharmacologically, ketogenesis can be induced by PPAR-alpha agonists that increase HMGCS2 expression or by SGLT2 inhibitors that shift metabolic flux toward fatty acid oxidation (PubMed PMID: 28414302). While therapeutic induction offers metabolic benefits, it requires careful monitoring to prevent pathological ketoacidosis, a life-threatening state of metabolic acidosis often associated with absolute or relative insulin deficiency (NIH, Diabetic Ketoacidosis). The targeting of this pathway remains a key area of interest for treating metabolic syndrome and nonalcoholic fatty liver disease by enhancing hepatic lipid oxidation.

Other names

3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2HMG-CoA synthase 23-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial)Ketogenesis-regulating enzyme

Induction of ketogenesis is primarily achieved through the transcriptional upregulation of HMGCS2 via Peroxisome proliferator-activated receptor alpha (PPAR-alpha) activation, or indirectly via SGLT2 inhibitors which lower the insulin-to-glucagon ratio, stimulating the release of fatty acids and subsequent hepatic ketone production.