The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis

Nat Commun. 2021 Nov 2;12(1):6315. doi: 10.1038/s41467-021-26638-5.


Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Here we describe a hepatic system in this context orchestrated by the transcriptional corepressor C-terminal binding protein 2 (CtBP2) that harbors metabolite-sensing capabilities. The repressor activity of CtBP2 is reciprocally regulated by NADH and acyl-CoAs. CtBP2 represses Forkhead box O1 (FoxO1)-mediated hepatic gluconeogenesis directly as well as Sterol Regulatory Element-Binding Protein 1 (SREBP1)-mediated lipogenesis indirectly. The activity of CtBP2 is markedly defective in obese liver reflecting the metabolic perturbations. Thus, liver-specific CtBP2 deletion promotes hepatic gluconeogenesis and accelerates the progression of steatohepatitis. Conversely, activation of CtBP2 ameliorates diabetes and hepatic steatosis in obesity. The structure-function relationships revealed in this study identify a critical structural domain called Rossmann fold, a metabolite-sensing pocket, that is susceptible to metabolic liabilities and potentially targetable for developing therapeutic approaches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / metabolism*
  • Animals
  • Cell Line
  • Co-Repressor Proteins / genetics
  • Co-Repressor Proteins / metabolism*
  • Disease Models, Animal
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology*
  • Gluconeogenesis
  • Glucose / metabolism*
  • Homeostasis
  • Humans
  • Lipids / physiology*
  • Lipogenesis
  • Liver / metabolism
  • Liver / pathology*
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Primary Cell Culture


  • Co-Repressor Proteins
  • Lipids
  • Alcohol Oxidoreductases
  • CTBP2 protein, human
  • Ctbp2 protein, mouse
  • Glucose