Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

J Clin Invest. 2014 Dec;124(12):5175-90. doi: 10.1172/JCI76388. Epub 2014 Oct 27.


Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide-induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / genetics
  • Acyl Coenzyme A / metabolism
  • Animals
  • Citric Acid Cycle / drug effects
  • Citric Acid Cycle / genetics
  • Dietary Fats / adverse effects*
  • Gluconeogenesis / drug effects
  • Gluconeogenesis / genetics
  • Glucose / genetics
  • Glucose / metabolism*
  • Hydroxymethylglutaryl-CoA Synthase / deficiency
  • Hydroxymethylglutaryl-CoA Synthase / genetics
  • Hydroxymethylglutaryl-CoA Synthase / metabolism
  • Hyperglycemia / chemically induced*
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism*
  • Hyperglycemia / pathology
  • Hypoglycemia / genetics
  • Hypoglycemia / metabolism
  • Hypoglycemia / pathology
  • Male
  • Metabolism, Inborn Errors / genetics
  • Metabolism, Inborn Errors / metabolism
  • Metabolism, Inborn Errors / pathology
  • Mice
  • Mice, Mutant Strains
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Non-alcoholic Fatty Liver Disease / chemically induced*
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology


  • Acyl Coenzyme A
  • Dietary Fats
  • Hydroxymethylglutaryl-CoA Synthase
  • Glucose

Supplementary concepts

  • 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 Deficiency