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Hepatic GSK3β-dependent CRY1 Degradation Contributes to Diabetic Hyperglycemia

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posted on 27.04.2022, 19:57 by Ye Young Kim, Hagoon Jang, Gung Lee, Yong Geun Jeon, Jee Hyung Sohn, Ji Seul Han, Won Taek Lee, Jeu Park, Jin Young Huh, Hahn Nahmgoong, Sang Mun Han, Jeesoo Kim, Minwoo Pak, Sun Kim, Jong-Seo Kim, Jae Bum Kim

Excessive hepatic glucose production (HGP) is a key factor promoting hyperglycemia in diabetes. Hepatic cryptochrome 1 (CRY1) plays an important role in maintaining glucose homeostasis by suppressing forkhead box protein O1 (FOXO1)-mediated HGP. Although downregulation of hepatic CRY1 appears to be associated with increased HGP, the mechanism(s) by which hepatic CRY1 dysregulation confers hyperglycemia in diabetic subjects is largely unknown. In this study, we demonstrate that a reduction in hepatic CRY1 protein is stimulated by elevated E3 ligase F-box and leucine-rich repeat protein 3 (FBXL3)-dependent proteasomal degradation in diabetic mice. In addition, we found that GSK3b-induced CRY1 phosphorylation potentiates FBXL3-dependent CRY1 degradation in the liver. Accordingly, in diabetic mice, GSK3b inhibitors effectively decreased HGP by facilitating the effect of CRY1-mediated FOXO1 degradation on glucose metabolism. Collectively, these data suggest that tight regulation of hepatic CRY1 protein stability is crucial for maintaining systemic glucose homeostasis. 

Funding

This study was supported by the National Research Foundation, funded by the Korean government (NRF-2020R1A3B2078617 to J.B.K. and MSIT; IBS-R008-D1 to J.-S.K.). Y.Y.K., Y.G.J., J.H.S., W.T.L., J.P., H.N.., and S.M.H were supported by the BK21 Plus program.

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