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Hyperglycemia is exacerbated by dysregulation of hepatic SREBP1c‐CRY1 signaling pathway

SREBP1c is a key transcription factor of lipogenesis to store excess energy in postprandial state. Although SREBP1c appears to be involved in suppression of hepatic gluconeogenesis, the molecular mechanism(s) by which insulin‐activated SREBP1c could repress hepatic gluconeogenesis is not thoroughly understood. Here, we demonstrate that CRY1 activation by insulin‐induced SREBP1c led to decrease hepatic gluconeogenesis through FOXO1 degradation. In accordance with these, SREBP1c−/−and CRY1−/− mice showed higher blood glucose than wild type (WT) mice during pyruvate tolerance test, accompanied with enhanced expression of PEPCK and G6Pase genes. Moreover, CRY1 promoted degradation of nuclear FOXO1 by MDM2, one of the ubiquitin E3 ligases, by enhancing binding of FOXO1 and MDM2. Although hepatic SREBP1c failed to upregulate CRY1 expression in db/db mice, overexpression of CRY1 led to attenuate hyperglycemia through reduction of hepatic FOXO1 protein as well as gluconeogenic gene expression. Collectively, these data suggest that insulin‐activated SREBP1c downregulates hepatic gluconeogenesis through CRY1‐mediated FOXO1 degradation and thereby dysregulation of SREBP1c‐CRY1 signaling cascade in liver could confer hyperglycemia in diabetic animals.