한빛사논문
- 조회759
Seungwon An1,10, Balachandar Nedumaran2,10, Hong Koh3,10, Dong Jin Joo4, Hyungjo Lee1, Chul-Seung Park5, Robert A. Harris6, Keong Sub Shin7,8, Ali R. Djalilian1 and Yong Deuk Kim 7,8,9
1Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA.
2Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
3Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Severance Children’s Hospital, Severance Pediatric Liver Disease Research Group, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
4Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
5School of Life Sciences and Cell Logistics Research Center, Gwangju Institute Science and Technology, Gwangju 61005, Republic of Korea.
6Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
7DUKSAN Institute of Biomedical and Life Science, Gwangmyeong 14348, Republic of Korea.
8Young Sciences, Inc., Bucheon 14449, Republic of Korea.
9Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, Republic of Korea.
10These authors contributed equally: Seungwon An, Balachandar Nedumaran, Hong Koh.
Corresponding author : Correspondence to Yong Deuk Kim.
Abstract
Melatonin is involved in the regulation of various biological functions. Here, we explored a novel molecular mechanism by which the melatonin-induced sestrin2 (SESN2)-small heterodimer partner (SHP) signaling pathway protects against fasting- and diabetes-mediated hepatic glucose metabolism. Various key gene expression analyses were performed and multiple metabolic changes were assessed in liver specimens and primary hepatocytes of mice and human participants. The expression of the hepatic cereblon (CRBN) and b-cell translocation gene 2 (BTG2) genes was significantly increased in fasting mice, diabetic mice, and patients with diabetes. Overexpression of Crbn and Btg2 increased hepatic gluconeogenesis by enhancing cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH), whereas this phenomenon was prominently ablated in Crbn null mice and Btg2-silenced mice. Interestingly, melatonin-induced SESN2 and SHP markedly reduced hepatic glucose metabolism in diabetic mice and primary hepatocytes, and this protective effect of melatonin was strikingly reversed by silencing Sesn2 and Shp. Finally, the melatonin-induced SESN2-SHP signaling pathway inhibited CRBN- and BTG2-mediated hepatic gluconeogenic gene transcription via the competition of BTG2 and the interaction of CREBH. Mitigation of the CRBN-BTG2-CREBH axis by the melatonin-SESN2-SHP signaling network may provide a novel therapeutic strategy to treat metabolic dysfunction due to diabetes.
논문정보
- Research article
- 2023년 07월 (BRIC 등록일 2023-07-25)
- 국내(교신)+국외 연구진
- 의약학 > 분자세포의학
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