The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease
Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-ch...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-08-01
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| Series: | JCI Insight |
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| Online Access: | https://doi.org/10.1172/jci.insight.140687 |
| _version_ | 1811227808997834752 |
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| author | Zhihong Yang Rana V. Smalling Yi Huang Yanchao Jiang Praveen Kusumanchi Will Bogaert Li Wang Don A. Delker Nicholas J. Skill Sen Han Ting Zhang Jing Ma Nazmul Huda Suthat Liangpunsakul |
| author_facet | Zhihong Yang Rana V. Smalling Yi Huang Yanchao Jiang Praveen Kusumanchi Will Bogaert Li Wang Don A. Delker Nicholas J. Skill Sen Han Ting Zhang Jing Ma Nazmul Huda Suthat Liangpunsakul |
| author_sort | Zhihong Yang |
| collection | DOAJ |
| description | Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp−/− mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERBα agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp−/− mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERBα is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erbα−/− hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBα agonist SR9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERBα/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERBα or CYP4A as the potential therapeutic targets for ALD. |
| first_indexed | 2024-04-12T09:47:00Z |
| format | Article |
| id | doaj.art-d5708828b4b84004958f756a2788b968 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T09:47:00Z |
| publishDate | 2021-08-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-d5708828b4b84004958f756a2788b9682022-12-22T03:37:55ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-08-01616The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver diseaseZhihong YangRana V. SmallingYi HuangYanchao JiangPraveen KusumanchiWill BogaertLi WangDon A. DelkerNicholas J. SkillSen HanTing ZhangJing MaNazmul HudaSuthat LiangpunsakulAlcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp−/− mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERBα agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp−/− mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERBα is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erbα−/− hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBα agonist SR9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERBα/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERBα or CYP4A as the potential therapeutic targets for ALD.https://doi.org/10.1172/jci.insight.140687Hepatology |
| spellingShingle | Zhihong Yang Rana V. Smalling Yi Huang Yanchao Jiang Praveen Kusumanchi Will Bogaert Li Wang Don A. Delker Nicholas J. Skill Sen Han Ting Zhang Jing Ma Nazmul Huda Suthat Liangpunsakul The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease JCI Insight Hepatology |
| title | The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease |
| title_full | The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease |
| title_fullStr | The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease |
| title_full_unstemmed | The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease |
| title_short | The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease |
| title_sort | role of shp rev erbα cyp4a axis in the pathogenesis of alcohol associated liver disease |
| topic | Hepatology |
| url | https://doi.org/10.1172/jci.insight.140687 |
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