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Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease

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-indu...

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Autores principales: Gao, Yongyao, Jiang, Xiaomeng, Yang, Daigang, Guo, Wentong, Wang, Dandan, Gong, Ke, Peng, Ying, Jiang, Hong, Shi, Cunyuan, Duan, Yajun, Chen, Yuanli, Han, Jihong, Yang, Xiaoxiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127324/
https://www.ncbi.nlm.nih.gov/pubmed/35620283
http://dx.doi.org/10.3389/fphar.2022.895710
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author Gao, Yongyao
Jiang, Xiaomeng
Yang, Daigang
Guo, Wentong
Wang, Dandan
Gong, Ke
Peng, Ying
Jiang, Hong
Shi, Cunyuan
Duan, Yajun
Chen, Yuanli
Han, Jihong
Yang, Xiaoxiao
author_facet Gao, Yongyao
Jiang, Xiaomeng
Yang, Daigang
Guo, Wentong
Wang, Dandan
Gong, Ke
Peng, Ying
Jiang, Hong
Shi, Cunyuan
Duan, Yajun
Chen, Yuanli
Han, Jihong
Yang, Xiaoxiao
author_sort Gao, Yongyao
collection PubMed
description 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 1α (HIF-1α), 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 β-oxidation through inducing peroxisome proliferator-activated receptor α (PPARα) 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-1α regulation. Taken together, our study demonstrates that activation of HIF-1α 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.
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spelling pubmed-91273242022-05-25 Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease Gao, Yongyao Jiang, Xiaomeng Yang, Daigang Guo, Wentong Wang, Dandan Gong, Ke Peng, Ying Jiang, Hong Shi, Cunyuan Duan, Yajun Chen, Yuanli Han, Jihong Yang, Xiaoxiao Front Pharmacol Pharmacology 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 1α (HIF-1α), 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 β-oxidation through inducing peroxisome proliferator-activated receptor α (PPARα) 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-1α regulation. Taken together, our study demonstrates that activation of HIF-1α 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. Frontiers Media S.A. 2022-05-10 /pmc/articles/PMC9127324/ /pubmed/35620283 http://dx.doi.org/10.3389/fphar.2022.895710 Text en Copyright © 2022 Gao, Jiang, Yang, Guo, Wang, Gong, Peng, Jiang, Shi, Duan, Chen, Han and Yang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Gao, Yongyao
Jiang, Xiaomeng
Yang, Daigang
Guo, Wentong
Wang, Dandan
Gong, Ke
Peng, Ying
Jiang, Hong
Shi, Cunyuan
Duan, Yajun
Chen, Yuanli
Han, Jihong
Yang, Xiaoxiao
Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease
title Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease
title_full Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease
title_fullStr Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease
title_full_unstemmed Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease
title_short Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease
title_sort roxadustat, a hypoxia-inducible factor 1α activator, attenuates both long- and short-term alcohol-induced alcoholic liver disease
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127324/
https://www.ncbi.nlm.nih.gov/pubmed/35620283
http://dx.doi.org/10.3389/fphar.2022.895710
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