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

Nat Commun. 2016 Jul 14:7:12180. doi: 10.1038/ncomms12180.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cryptochromes / genetics
  • Cryptochromes / metabolism*
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / pathology
  • Disease Models, Animal
  • Feeding Behavior*
  • Forkhead Box Protein O1 / metabolism*
  • Gene Expression Regulation / drug effects
  • Gluconeogenesis / drug effects
  • Glucose / biosynthesis*
  • Glucose / metabolism
  • HEK293 Cells
  • Humans
  • Hyperglycemia / complications
  • Hyperglycemia / pathology
  • Insulin / pharmacology
  • Liver / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Models, Biological
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Signal Transduction*
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitination
  • Up-Regulation

Substances

  • Cry1 protein, mouse
  • Cryptochromes
  • Forkhead Box Protein O1
  • Insulin
  • Sterol Regulatory Element Binding Protein 1
  • Ubiquitin
  • Proto-Oncogene Proteins c-mdm2
  • Proteasome Endopeptidase Complex
  • Glucose