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

Motohiro Sekiya (), Kenta Kainoh, Takehito Sugasawa, Ryunosuke Yoshino, Takatsugu Hirokawa, Hiroaki Tokiwa, Shogo Nakano, Satoru Nagatoishi, Kouhei Tsumoto, Yoshinori Takeuchi, Takafumi Miyamoto, Takashi Matsuzaka and Hitoshi Shimano
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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
Yoshinori Takeuchi: University of Tsukuba
Takafumi Miyamoto: University of Tsukuba
Takashi Matsuzaka: University of Tsukuba
Hitoshi Shimano: University of Tsukuba

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26638-5

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