SREBP1c-CRY1 signalling represses hepatic glucose production by promoting FOXO1 degradation during refeeding

• Published in: Nature communications Vol. 7; no. 1; p. 12180
• Main Authors: Jang, Hagoon, Lee, Gha Young, Selby, Christopher P., Lee, Gung, Jeon, Yong Geun, Lee, Jae Ho, Cheng, Kenneth King Yip, Titchenell, Paul, Birnbaum, Morris J., Xu, Aimin, Sancar, Aziz, Kim, Jae Bum
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.07.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 59; 59/5; 631/443/319; 631/45/612/822; 631/80/86; 692/308; 82; 96; 96/1; 96/95; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12180

SREBP1c is a key lipogenic transcription factor activated by insulin in the postprandial state. Although SREBP1c appears to be involved in suppression of hepatic gluconeogenesis, the molecular mechanism is not thoroughly understood. Here we show that CRY1 is activated by insulin-induced SREBP1c and decreases hepatic gluconeogenesis through FOXO1 degradation, at least, at specific circadian time points. SREBP1c −/− and CRY1 −/− mice show higher blood glucose than wild-type (WT) mice in pyruvate tolerance tests, accompanied with enhanced expression of PEPCK and G6Pase genes. CRY1 promotes degradation of nuclear FOXO1 by promoting its binding to the ubiquitin E3 ligase MDM2. Although SREBP1c fails to upregulate CRY1 expression in db/db mice, overexpression of CRY1 attenuates hyperglycaemia through reduction of hepatic FOXO1 protein and gluconeogenic gene expression. These data suggest that insulin-activated SREBP1c downregulates gluconeogenesis through CRY1-mediated FOXO1 degradation and that dysregulation of hepatic SREBP1c-CRY1 signalling may contribute to hyperglycaemia in diabetic animals. The clock protein Cry regulates hepatic glucose metabolism. Here the authors show that SREBP1c, activated by insulin signalling after feeding, directly regulates Cry transcription at specific circadian time points, and that Cry represses hepatic glucose production by promoting proteasomal degradation of Foxo1.