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

Hagoon Jang, Gha Young Lee, Christopher P. Selby, Gung Lee, Yong Geun Jeon, Jae Ho Lee, Kenneth King Yip Cheng, Paul Titchenell, Morris J. Birnbaum, Aimin Xu, Aziz Sancar and Jae Bum Kim ()
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Hagoon Jang: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University
Gha Young Lee: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University
Christopher P. Selby: University of North Carolina School of Medicine
Gung Lee: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University
Yong Geun Jeon: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University
Jae Ho Lee: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University
Kenneth King Yip Cheng: The University of Hong Kong
Paul Titchenell: The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania
Morris J. Birnbaum: The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania
Aimin Xu: The University of Hong Kong
Aziz Sancar: University of North Carolina School of Medicine
Jae Bum Kim: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12180

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