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.
Highlights
Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis
We attempted to decipher the C-terminal binding protein 2 (CtBP2) cistrome in normal liver tissues using chromatin immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIPseq) since the global transcriptional landscape would provide clues to the molecular basis regulated by CtBP2 in an unbiased manner
The analysis of CtBP2-binding sites with transcriptional elements revealed that CtBP2 is more frequently recruited into transcriptional start site (TSS) ChIP peaks are observed on gene bodies of a certain set of genes (Supplementary Fig. 1a, b)
Summary
Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Numerous metabolic intermediates generated throughout the complex metabolic networks have emerged as multifunctional regulators orchestrating cellular homeostasis: epigenetic regulation, modulation of enzymatic activities, posttranslational modification, and so forth[1,2] This metabolite-driven system has been reported to influence a wide variety of biological processes and diseases. Considering the functional interdependence between fatty acid metabolism and NADH/NAD+ regulation[17] and a role for NADH/NAD+ ratio associated with mitochondrial activity in hepatic glucose production[18,19], pyridine dinucleotides may be involved These metabolic intermediates and their molecular targets would be of particular interest in understanding the dysregulation of hepatic glucose and lipid metabolism
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