An Seungwon, Nedumaran Balachandar, Oh Hangaram, Park Taehyun, Park Chul-Seung, Djalilian Ali R, Shin Sooyong, Chung Taehoon, Kim Yong Deuk
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois 60612, USA; Clinical Stem Cell Laboratory, UI Blood & Marrow Transplant Program, University of Illinois Hospital and Health Sciences System, Chicago, Illinois 60612, USA.
Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
BMB Rep. 2024 Dec;57(12):533-538. doi: 10.5483/BMBRep.2024-0068.
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 expressions 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 also 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. [BMB Reports 2024; 57(12): 533-538].
大脑酮体结合蛋白（CRBN）是一种广泛表达的蛋白质，参与关键的生理过程。本研究揭示了CRBN在糖尿病状态下通过环磷酸腺苷（cAMP）途径调控肝成纤维细胞生长因子23（FGF23）表达和产生中的作用。糖尿病小鼠和经福斯高林（FSK）处理的原代肝细胞中，肝脏Crbn、阴阳1（Yy1）和Fgf23基因的表达显著增加，这与FGF23产生的升高相关。Crbn和Yy1的过表达通过上调YY1基因表达增加了肝脏FGF23和细胞因子，而在Crbn和Yy1沉默的小鼠及原代肝细胞中，这种表达降低。此外，我们还发现CRBN介导的肝脏FGF23调控涉及YY1募集到Fgf23基因启动子，荧光素酶报告基因检测、缺失研究和突变分析证明了这一点。这些发现确定CRBN和YY1是糖尿病中糖异生信号驱动的FGF23产生和炎症的关键促成因素，突出了它们作为治疗糖尿病等代谢紊乱疾病治疗靶点的潜力。[《BMB报告》2024年；57(第12期):533 - 538]
