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

Author

Listed:
  • Motohiro Sekiya

    (University of Tsukuba)

  • Kenta Kainoh

    (University of Tsukuba)

  • Takehito Sugasawa

    (University of Tsukuba)

  • Ryunosuke Yoshino

    (University of Tsukuba)

  • Takatsugu Hirokawa

    (University of Tsukuba)

  • Hiroaki Tokiwa

    (Rikkyo University, Nishi-Ikebukuro)

  • Shogo Nakano

    (University of Shizuoka)

  • Satoru Nagatoishi

    (The University of Tokyo)

  • Kouhei Tsumoto

    (The University of Tokyo
    The University of Tokyo)

  • Yoshinori Takeuchi

    (University of Tsukuba)

  • Takafumi Miyamoto

    (University of Tsukuba)

  • Takashi Matsuzaka

    (University of Tsukuba
    University of Tsukuba)

  • Hitoshi Shimano

    (University of Tsukuba)

Abstract

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.

Suggested Citation

  • Motohiro Sekiya & Kenta Kainoh & Takehito Sugasawa & Ryunosuke Yoshino & Takatsugu Hirokawa & Hiroaki Tokiwa & Shogo Nakano & Satoru Nagatoishi & Kouhei Tsumoto & Yoshinori Takeuchi & Takafumi Miyamot, 2021. "The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26638-5
    DOI: 10.1038/s41467-021-26638-5
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