Hepatic GSK3β-Dependent CRY1 Degradation Contributes to Diabetic Hyperglycemia

Author:

Kim Ye Young1,Jang Hagoon1,Lee Gung1,Jeon Yong Geun1,Sohn Jee Hyung1,Han Ji Seul1,Lee Won Taek1,Park Jeu1,Huh Jin Young1,Nahmgoong Hahn1,Han Sang Mun1,Kim Jeesoo2ORCID,Pak Minwoo3,Kim Sun345,Kim Jong-Seo2,Kim Jae Bum1

Affiliation:

1. 1Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea

2. 2Center for RNA Research, Institute for Basic Science, School of Biological Sciences, Seoul, South Korea

3. 3Department of Computer Science and Engineering, Institute of Engineering Research, Seoul National University, Seoul, South Korea

4. 4Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, South Korea

5. 5Interdisciplinary Program in Artificial Intelligence, Seoul National University, Seoul, South Korea

Abstract

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 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 subjects with diabetes 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 GSK3β-induced CRY1 phosphorylation potentiates FBXL3-dependent CRY1 degradation in the liver. Accordingly, in diabetic mice, GSK3β 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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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