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

Hagoon Jang1, Gha Young Lee1, Christopher P Selby2

  • 1School of Biological Sciences, Institute of Molecular Biology and Genetics, Center for Adipose Tissue Remodeling, Seoul National University, Seoul 151-742, Korea.

Nature Communications
|July 15, 2016
PubMed

Insights

Insulin activates SREBP1c, which then activates CRY1 to reduce blood glucose by degrading FOXO1. This pathway

Area of Science:

  • Molecular Endocrinology
  • Metabolic Regulation
  • Chronobiology

Background:

  • Sterol regulatory element-binding protein 1c (SREBP1c) is a key lipogenic transcription factor activated by insulin.
  • The precise molecular mechanism by which SREBP1c suppresses hepatic gluconeogenesis remains unclear.
  • FOXO1 is a crucial regulator of gluconeogenic gene expression.

Purpose of the Study:

  • To elucidate the molecular mechanism linking insulin-activated SREBP1c to the suppression of hepatic gluconeogenesis.
  • To investigate the role of CRY1 in mediating the effects of SREBP1c on gluconeogenesis.
  • To explore the potential contribution of the SREBP1c-CRY1-FOXO1 axis to hyperglycemia in diabetes.

Main Methods:

  • Utilized SREBP1c(-/-) and CRY1(-/-) knockout mouse models.
  • Performed pyruvate tolerance tests to assess glucose metabolism.
  • Analyzed the expression of gluconeogenic genes (PEPCK, G6Pase).
  • Investigated protein-protein interactions between CRY1, FOXO1, and MDM2.
  • Examined the SREBP1c-CRY1 pathway in db/db diabetic mouse models.

Main Results:

  • SREBP1c activation by insulin leads to CRY1 upregulation.
  • CRY1 promotes the degradation of nuclear FOXO1 by facilitating its binding to MDM2, a ubiquitin E3 ligase.
  • Mice lacking SREBP1c or CRY1 exhibited elevated blood glucose levels and increased gluconeogenic gene expression.
  • Overexpression of CRY1 in diabetic mice reduced hyperglycemia by decreasing FOXO1 protein and gluconeogenic gene expression.
  • SREBP1c failed to upregulate CRY1 in db/db mice, indicating pathway dysregulation.

Conclusions:

  • Insulin-activated SREBP1c downregulates hepatic gluconeogenesis via CRY1-mediated FOXO1 degradation.
  • The SREBP1c-CRY1 signaling pathway plays a critical role in glucose homeostasis.
  • Dysregulation of this pathway may contribute to hyperglycemia in diabetic conditions.

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