Ketogenesis pathway

Ketogenesis is a metabolic pathway primarily occurring in the liver mitochondria that converts fatty acids into ketone bodies—acetoacetate, beta-hydroxybutyrate (BHB), and acetone—to serve as alternative energy substrates when glucose is scarce (StatPearls, 2023). The rate-limiting step of this pathway is catalyzed by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2), which is transcriptionally regulated by PPAR-alpha (Nature Reviews Endocrinology, 2017). Beyond their role as fuel for the brain, heart, and skeletal muscle, ketone bodies act as signaling molecules, inhibiting histone deacetylases (HDACs) and modulating inflammation and oxidative stress (Cell Metabolism, 2014). In clinical practice, the ketogenesis pathway is therapeutically targeted through the ketogenic diet for refractory epilepsy and is significantly influenced by SGLT2 inhibitors, which can lead to increased BHB levels and, in rare cases, euglycemic ketoacidosis (Diabetes Care, 2015). Emerging research also explores the pathway's role in heart failure, where ketones provide a more oxygen-efficient fuel, and in oncology, where metabolic reprogramming may limit tumor growth (JACC, 2020).

Other names

Ketone body biosynthesisKetone metabolismHMG-CoA pathway (ketogenic)

Modulation of ketone body production and utilization to provide alternative energy substrates or signaling molecules.