이철호 (한국생명공학연구원)

한빛사논문

조회235

한국생명공학연구원

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Redox Biol., Mar 05 2024, 71 S2213-2317(24)00083-1 | https://doi.org/10.1016/j.redox.2024.103107 ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress

Yoon Seok Jung ^a,1, Kamalakannan Radhakrishnan ^a,1, Seddik Hammad ^b,c, Sebastian Müller ^d, Johannes Müller ^d, Jung-Ran Noh ^e, Jina kim ^f, In-Kyu Lee ^g,h, Sung Jin Cho ⁱ, Don-Kyu Kim^j, Yong-Hoon Kim ^e,k, Chul-Ho Lee ^e,k, Steven Dooley ^b, Hueng-Sik Choi^a

^aHost-derived Antiviral Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea

^bMolecular Hepatology Section, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3 (H42, Floor 4), 68167, Mannheim, Germany

^cDepartment of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt

^dCenter for Alcohol Research (CAR), University of Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany

^eDepartment of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea

^fNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea

^gDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea

^hResearch Institute of Aging and Metabolism, Kyungpook National University, Daegu 41940, Republic of Korea

ⁱCenter for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea

^jHost-derived Antiviral Research Center, Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju, 61186, Republic of Korea

^kLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea

¹These authors contributed equally to this work.

Corresponding authors: Yong-Hoon Kim, Chul-Ho Lee, Steven Dooley, Hueng-Sik Choi

Abstract

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-14)
연구진국내(교신)+국외 연구진
분야 생명과학 > 수의학

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