Host-derived Antiviral Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea
Kamalakannan Radhakrishnan
Host-derived Antiviral Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea
Seddik Hammad
Molecular Hepatology Section, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3 (H42, Floor 4), 68167, Mannheim, Germany; Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt
Sebastian Müller
Center for Alcohol Research (CAR), University of Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany
Johannes Müller
Center for Alcohol Research (CAR), University of Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany
Jung-Ran Noh
Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea
Jina kim
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
In-Kyu Lee
Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea; Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41940, Republic of Korea
Sung Jin Cho
Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
Don-Kyu Kim
Host-derived Antiviral Research Center, Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju, 61186, Republic of Korea
Yong-Hoon Kim
Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea; Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea; Corresponding author. Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
Chul-Ho Lee
Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea; Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea; Corresponding author. Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
Host-derived Antiviral Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea; Corresponding author. Chonnam National University, Gwangju 61186, Republic of Korea.
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.
