Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling

• Published in: Cell 2017-11, Vol.171 (4), p.824-835.e18
• Main Authors: Langlet, Fanny, Haeusler, Rebecca A., Lindén, Daniel, Ericson, Elke, Norris, Tyrrell, Johansson, Anders, Cook, Joshua R., Aizawa, Kumiko, Wang, Ling, Buettner, Christoph, Accili, Domenico
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Cells, Cultured; diabetes; drug therapy; Forkhead Box Protein O1 - antagonists & inhibitors; Forkhead Box Protein O1 - chemistry; Glucokinase - genetics; Glucokinase - metabolism; Glucose - metabolism; Glucose-6-Phosphatase - genetics; Glucose-6-Phosphatase - metabolism; HEK293 Cells; hepatic glucose production; Hepatocytes - enzymology; Hepatocytes - metabolism; hepatosteatosis; Histone Deacetylases - metabolism; Humans; Insulin Resistance; insulin sensitizers; lipogenesis; Lipogenesis - drug effects; Mice; Mice, Knockout; Phosphorylation; Promoter Regions, Genetic; Repressor Proteins - genetics; Repressor Proteins - metabolism; selective modulators; small molecule inhibitor; transcription repressor
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.09.045

Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here, we report that SIN3A is the insulin-sensitive FOXO1 corepressor of glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of glucokinase without affecting other FOXO1 target genes and lowers glycemia without concurrent steatosis. To extend this work, we executed a small-molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes. In addition to identifying a novel mode of insulin action, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out adverse effects of insulin sensitizers. [Display omitted] •Discovery of SIN3a as the FOXO corepressor of hepatic glucokinase•SIN3a regulates hepatic insulin sensitivity•Corepressor clearance as a novel mechanism of gene induction by insulin•Selective targeting of the activator and repressor functions of FOXO1 The transcriptional output of FOXO1 can be selectively modulated in a way that might reduce adverse effects of insulin sensitizers.