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The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease.

ABSTRACT: 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.

SUBMITTER: Yang Z

PROVIDER: S-EPMC8410014 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα-/- mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα-/- mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα-/- microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα-/- mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα-/- mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

Project description:BackgroundThe nuclear receptor REV-ERBα (nuclear receptor subfamily 1, Group D member 1, NR1D1) is one of the essential components of the circadian clock which modulates cell proliferation, glucose metabolism, inflammation, and many other biological processes. Modulation of these processes are also relevant to cancer development. Previous studies have suggested that activation of REV-ERBα correlates with cancer cell senescence and death, but how REV-ERBα play roles in tumor progression require further elucidation.MethodsWe investigated the expression of REV-ERBα in clinical samples by immunohistochemistry (IHC). REV-ERBα is downregulated by shorth hairpin RNA (shRNA). The gene expression level of each group was detected by Western blot analysis. The effects of REV-ERBα downregulation on apoptosis and cell cycles was assessed by flow cytometry assay. A549 cell growth curve under different treatments measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Cell invasion ability under different treatments was measured by Transwell assay. Immunostaining analysis was also used for evaluating the effects of downregulation of REV-ERBα on nuclear factor-κB (NF-κB).ResultsCompared to 81.8% (54/66) of samples exhibiting a lower expression level of REV-ERBα in cancer tissue than in paired normal tissue, only 18.2% (12/66) were higher or equally expressed in lung cancer tissue. Furthermore, downregulation of REV-ERBα by RNA interference can significantly enhance the transcription of nuclear factor-κB (NF-κB), while the expression of p53 remained the same. Downregulation of REV-ERBα was also shown to stimulate the invasion and promote the proliferation of lung adenocarcinoma cell line A549.ConclusionsOur findings suggest that tumorigenesis and progression of lung carcinoma is relevant to downregulation or inhibition of REV-ERBα. This pathophysiological process also correlates with regulation of the NF-κB signaling pathway, indicating that REV-ERBα is a potential target of lung cancer therapy.

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The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease.

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