Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
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.
生物系统感知和响应代谢扰动对于维持细胞内稳态至关重要。在这里，我们描述了一个由转录共抑制因子 C 端结合蛋白 2 (CtBP2) 协调的肝系统，该系统具有代谢物感应能力。CtBP2 的抑制活性受到 NADH 和酰基辅酶 A 的反向调节。CtBP2 直接抑制 FoxO1 介导的肝糖异生，以及间接抑制 SREBP1 介导的脂肪生成。肥胖肝脏中 CtBP2 的活性明显缺陷，反映了代谢扰动。因此，肝特异性 CtBP2 缺失促进肝糖异生，并加速脂肪性肝炎的进展。相反，CtBP2 的激活可改善肥胖症中的糖尿病和肝脂肪变性。本研究揭示的结构-功能关系确定了一个关键的结构域，称为罗斯曼折叠，一个代谢物感应口袋，易受代谢缺陷的影响，可能成为开发治疗方法的潜在靶点。
