title: SREBP1c-CRY1 signalling represses hepatic glucose production by promoting FOXO1 degradation during refeeding.
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.
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University, Seoul 151-742, Korea.
authors.forename: Hagoon
authors.initials: H
authors.lastname: Jang
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University, Seoul 151-742, Korea.
authors.forename: Gha Young
authors.initials: GY
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, CB # 7260, Chapel Hill, North Carolina 27599-7260, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Selby
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University, Seoul 151-742, Korea.
authors.forename: Gung
authors.initials: G
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University, Seoul 151-742, Korea.
authors.forename: Yong Geun
authors.initials: YG
authors.lastname: Jeon
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Medicine, The University of Hong Kong, Hong Kong, 999077, China.
authors.forename: Kenneth King Yip
authors.initials: KK
authors.lastname: Cheng
authors.affiliation: The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Titchenell
authors.affiliation: The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Morris J
authors.identifier: 0000-0001-9972-8680
authors.initials: MJ
authors.lastname: Birnbaum
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Medicine, The University of Hong Kong, Hong Kong, 999077, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, CB # 7260, Chapel Hill, North Carolina 27599-7260, USA.
authors.forename: Aziz
authors.initials: A
authors.lastname: Sancar
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jae Bum
authors.initials: JB
authors.lastname: Kim
mesh_terms: D000818:Animals; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology; D004195:Disease Models, Animal; D005247:Feeding Behavior; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000096:biosynthesis* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: C538964:Cry1 protein, mouse; D056931:Cryptochromes; D000071161:Forkhead Box Protein O1; D007328:Insulin; D051780:Sterol Regulatory Element Binding Protein 1; D025801:Ubiquitin; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex; D005947:Glucose