Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Korea.
Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea.
BMB Rep. 2021 Apr;54(4):221-226. doi: 10.5483/BMBRep.2021.54.4.215.
Hepcidin (HAMP) is synthesized in the liver. It is a key ironregulatory hormone that controls systemic iron homeostasis. Cereblon (CRBN) and Kruppel-like factor 15 (KLF15) are known to regulate diverse physiological functions. In this study, we investigated the role of CRBN on hepatic hepcidin gene expression and production under gluconeogenic stimuli. Fasted mice as well as forskolin (FSK)- and glucagon (GLU)-treated mice had reduced serum iron levels but increased expression levels of hepatic Crbn and Klf15 and hepcidin secretion. MicroRNA (miRNA) expression analysis of fasted and Ad-Crbninfected mice revealed significant reduction of microRNA-639 (miR-639). Hepatic overexpression of Crbn elevated hepcidin expression and production along with Klf15 gene expression, whereas knockdown of Crbn and Klf15 markedly decreased FSK- and fasting-mediated induction of hepcidin gene expression and its biosynthesis in mouse livers and primary hepatocytes. Moreover, expression of KLF15 significantly increased the activity of hepcidin reporter gene. It was exclusively dependent on the KLF15-binding site identified within the hepcidin gene promoter. Overall, this study demonstrates that CRBN and KLF15 are novel mediators of gluconeogenic signal-induced hepcidin gene expression and production. Thus, CRBN and KLF15 might be novel potential therapeutic targets to intervene metabolic dysfunction. [BMB Reports 2021; 54(4): 221-226].
亚铁调素（HAMP）在肝脏中合成。它是一种关键的铁调节激素，可控制全身铁稳态。已知 cereblon（CRBN）和 Krüppel 样因子 15（KLF15）可调节多种生理功能。在这项研究中，我们研究了 CRBN 在糖异生刺激下对肝脏 hepcidin 基因表达和产生的作用。禁食小鼠以及 forskolin（FSK）和胰高血糖素（GLU）处理的小鼠的血清铁水平降低，但肝脏 Crbn 和 Klf15 的表达水平和 hepcidin 分泌增加。禁食和 Ad-Crbn 感染小鼠的 microRNA（miRNA）表达分析显示，microRNA-639（miR-639）显著减少。肝内过表达 Crbn 可升高 hepcidin 的表达和产生，同时升高 Klf15 基因表达，而 Crbn 和 Klf15 的敲低则显著降低 FSK 和禁食介导的小鼠肝脏和原代肝细胞中 hepcidin 基因表达及其生物合成的诱导。此外，KLF15 的表达显著增加了 hepcidin 报告基因的活性。它完全依赖于在 hepcidin 基因启动子内鉴定的 KLF15 结合位点。总之，本研究表明 CRBN 和 KLF15 是糖异生信号诱导 hepcidin 基因表达和产生的新型介质。因此，CRBN 和 KLF15 可能是干预代谢功能障碍的新的潜在治疗靶点。[BMB 报告 2021；54(4): 221-226]。
