Cereblon regulates the production of hepatic fibroblast growth factor 23 in diabetes |
Seungwon An3,4 (Doctor), Balachanda Nedumaran5 (Doctor), Hangaram Oh1,2 (Research worker), Taehyun Park1,2 (Research worker), Chul-Seung Park6 (Professor), Ali R. Djalilian3 (Professor), Sooyong Shin1,2 (Doctor), Taehoon Chung1,2 (Research worker), Yong Deuk Kim 1,2,* (Doctor) |
1DUKSAN Institute of Biomedical and Life Science, DUKSAN Institute of Biomedical and Life Science, 2Young Sciences, Inc., Young Sciences, Inc., 3Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 4Clinical Stem Cell laboratory, University of Illinois Hospital and Health Sciences System, 5Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, 6School of Life Sciences and Cell Logistics Research Center, Gwangju Institute Science and Technology |
Abstract
Cereblon (CRBN) is an extensively expressed protein involved in crucial physiological processes. This study reveals CRBN's role in governing hepatic fibroblast growth factor 23 (FGF23) expression and production via the cyclic adenosine monophosphate (cAMP) pathway in diabetic conditions. The expression of hepatic Crbn, Yin Yang 1 (Yy1), and Fgf23 genes were significantly increased in diabetic mice and forskolin (FSK)-treated primary hepatocytes, correlating with elevated FGF23 production. Overexpression of Crbn and Yy1 increased hepatic FGF23 and cytokines by upregulating YY1 gene expression, which was reduced in Crbn- and Yy1-silenced mice and primary hepatocytes. Besides, we found that CRBN-mediated regulation of hepatic FGF23 involved YY1 recruitment to the Fgf23 gene promoters, evidenced by reporter assays, deletion studies, and mutant analyses. These findings identify CRBN and YY1 as key contributors to gluconeogenic signaling-driven FGF23 production and inflammation in diabetes, highlighting their potential as therapeutic targets for addressing metabolic disorders like diabetes.
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Abstract, Accepted Manuscript [Submitted on May 8, 2024, Accepted on October 2, 2024] |
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