PMID- 35620283 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 13 DP - 2022 TI - Roxadustat, a Hypoxia-Inducible Factor 1alpha Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease. PG - 895710 LID - 10.3389/fphar.2022.895710 [doi] LID - 895710 AB - Alcoholic liver disease (ALD) is a worldwide healthcare problem featured by inflammation, reactive oxygen species (ROS), and lipid dysregulation. Roxadustat is used for chronic kidney disease anemia treatment. As a specific inhibitor of prolyl hydroxylase, it can maintain high levels of hypoxia-inducible factor 1alpha (HIF-1alpha), through which it can further influence many important pathways, including the three featured in ALD. However, its effects on ALD remain to be elucidated. In this study, we used chronic and acute ALD mouse models to investigate the protective effects of roxadustat in vivo. Our results showed that long- and short-term alcohol exposure caused rising activities of serum transaminases, liver lipid accumulation, and morphology changes, which were reversed by roxadustat. Roxadustat-reduced fatty liver was mainly contributed by the reducing sterol-responsive element-binding protein 1c (SREBP1c) pathway, and enhancing beta-oxidation through inducing peroxisome proliferator-activated receptor alpha (PPARalpha) and carnitine palmitoyltransferase 1A (CPT1A) expression. Long-term alcohol treatment induced the infiltration of monocytes/macrophages to hepatocytes, as well as inflammatory cytokine expression, which were also blocked by roxadustat. Moreover, roxadustat attenuated alcohol caused ROS generation in the liver of those two mouse models mainly by reducing cytochrome P450 2E1 (CYP2E1) and enhancing superoxidase dismutase 1 (SOD1) expression. In vitro, we found roxadustat reduced inflammation and lipid accumulation mainly via HIF-1alpha regulation. Taken together, our study demonstrates that activation of HIF-1alpha can ameliorate ALD, which is contributed by reduced hepatic lipid synthesis, inflammation, and oxidative stress. This study suggested that roxadustat could be a potential drug for ALD treatment. CI - Copyright (c) 2022 Gao, Jiang, Yang, Guo, Wang, Gong, Peng, Jiang, Shi, Duan, Chen, Han and Yang. FAU - Gao, Yongyao AU - Gao Y AD - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. FAU - Jiang, Xiaomeng AU - Jiang X AD - Zhejiang Jianfeng Pharmaceutical Co., Ltd., Jinhua, China. FAU - Yang, Daigang AU - Yang D AD - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. FAU - Guo, Wentong AU - Guo W AD - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. FAU - Wang, Dandan AU - Wang D AD - School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China. FAU - Gong, Ke AU - Gong K AD - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. FAU - Peng, Ying AU - Peng Y AD - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. FAU - Jiang, Hong AU - Jiang H AD - Zhejiang Jianfeng Pharmaceutical Co., Ltd., Jinhua, China. FAU - Shi, Cunyuan AU - Shi C AD - Zhejiang Jianfeng Pharmaceutical Co., Ltd., Jinhua, China. FAU - Duan, Yajun AU - Duan Y AD - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. FAU - Chen, Yuanli AU - Chen Y AD - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. FAU - Han, Jihong AU - Han J AD - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. AD - College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China. FAU - Yang, Xiaoxiao AU - Yang X AD - Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. LA - eng PT - Journal Article DEP - 20220510 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC9127324 OTO - NOTNLM OT - ALD OT - HIF-1alpha OT - fatty liver OT - inflammation OT - oxidative stress OT - roxadustat COIS- XJ, HJ, and CS are employed by Zhejiang Jianfeng Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/05/28 06:00 MHDA- 2022/05/28 06:01 PMCR- 2022/05/10 CRDT- 2022/05/27 02:26 PHST- 2022/03/14 00:00 [received] PHST- 2022/04/11 00:00 [accepted] PHST- 2022/05/27 02:26 [entrez] PHST- 2022/05/28 06:00 [pubmed] PHST- 2022/05/28 06:01 [medline] PHST- 2022/05/10 00:00 [pmc-release] AID - 895710 [pii] AID - 10.3389/fphar.2022.895710 [doi] PST - epublish SO - Front Pharmacol. 2022 May 10;13:895710. doi: 10.3389/fphar.2022.895710. eCollection 2022.