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생화학분자생물학회 (Korean Society for Biochemistry and Molecular Biology)
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Gluconeogenic signals regulate hepcidin gene expression via a CRBN-KLF15 axis

  • Jo, Jeong-Rang (Research Institute of Aging and Metabolism, Kyungpook National University) ;
  • Lee, Sung-Eun (Department of Applied Biosciences, Kyungpook National University) ;
  • An, Seungwon (Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago) ;
  • Nedumaran, Balachandar (Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus) ;
  • Ghosh, Swati (Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus) ;
  • Park, Keun-Gyu (Research Institute of Aging and Metabolism, Kyungpook National University) ;
  • Kim, Yong Deuk (Research Institute of Aging and Metabolism, Kyungpook National University)
  • 투고 : 2020.09.29
  • 심사 : 2021.03.10
  • 발행 : 2021.04.30
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초록

Hepcidin (HAMP) is synthesized in the liver. It is a key iron-regulatory 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-Crbn-infected 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.

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과제정보

This research was supported by Kyungpook National University Development Project Research Fund, 2018 (to Y.D.K.).

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