Loss of heat shock factor 1 promotes hepatic stellate cell activation and drives liver fibrosis

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dc.contributor.authorChoudhury, Asmita
dc.contributor.authorRatna, Anuradha
dc.contributor.authorLim, Arlene
dc.contributor.authorSebastian, Rebecca M
dc.contributor.authorMoore, Christopher L
dc.contributor.authorFilliol, Aveline A
dc.contributor.authorBledsoe, Jacob
dc.contributor.authorDai, Chengkai
dc.contributor.authorSchwabe, Robert F
dc.contributor.authorShoulders, Matthew D
dc.contributor.authorMandrekar, Pranoti
dc.contributor.departmentMedicineen_US
dc.contributor.departmentPathologyen_US
dc.date.accessioned2024-01-10T16:27:46Z
dc.date.available2024-01-10T16:27:46Z
dc.date.issued2022-08-09
dc.description.abstractLiver fibrosis is an aberrant wound healing response that results from chronic injury and is mediated by hepatocellular death and activation of hepatic stellate cells (HSCs). While induction of oxidative stress is well established in fibrotic livers, there is limited information on stress-mediated mechanisms of HSC activation. Cellular stress triggers an adaptive defense mechanism via master protein homeostasis regulator, heat shock factor 1 (HSF1), which induces heat shock proteins to respond to proteotoxic stress. Although the importance of HSF1 in restoring cellular homeostasis is well-established, its potential role in liver fibrosis is unknown. Here, we show that HSF1 messenger RNA is induced in human cirrhotic and murine fibrotic livers. Hepatocytes exhibit nuclear HSF1, whereas stellate cells expressing alpha smooth muscle actin do not express nuclear HSF1 in human cirrhosis. Interestingly, despite nuclear HSF1, murine fibrotic livers did not show induction of HSF1 DNA binding activity compared with controls. HSF1-deficient mice exhibit augmented HSC activation and fibrosis despite limited pro-inflammatory cytokine response and display delayed fibrosis resolution. Stellate cell and hepatocyte-specific HSF1 knockout mice exhibit higher induction of profibrogenic response, suggesting an important role for HSF1 in HSC activation and fibrosis. Stable expression of dominant negative HSF1 promotes fibrogenic activation of HSCs. Overactivation of HSF1 decreased phosphorylation of JNK and prevented HSC activation, supporting a protective role for HSF1. Our findings identify an unconventional role for HSF1 in liver fibrosis. Conclusion: Our results show that deficiency of HSF1 is associated with exacerbated HSC activation promoting liver fibrosis, whereas activation of HSF1 prevents profibrogenic HSC activation.en_US
dc.identifier.citationChoudhury A, Ratna A, Lim A, Sebastian RM, Moore CL, Filliol AA, Bledsoe J, Dai C, Schwabe RF, Shoulders MD, Mandrekar P. Loss of heat shock factor 1 promotes hepatic stellate cell activation and drives liver fibrosis. Hepatol Commun. 2022 Oct;6(10):2781-2797. doi: 10.1002/hep4.2058. Epub 2022 Aug 9. PMID: 35945902; PMCID: PMC9512451.en_US
dc.identifier.doi10.1002/hep4.2058en_US
dc.identifier.eissn2471-254X
dc.identifier.journalHepatology communications
dc.identifier.pmid35945902
dc.identifier.urihttps://hdl.handle.net/20.500.14038/52932
dc.language.isoenen_US
dc.relation.ispartofHepatology Communicationsen_US
dc.relation.urlhttps://doi.org/10.1002/hep4.2058en_US
dc.rightsThis is an open access article under the terms of the Creative Commons Attribution- NonCommercial- NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made. © 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.en_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.source.beginpage2781
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.endpage2797
dc.source.issue10
dc.source.journaltitleHepatology communications
dc.source.volume6
dc.titleLoss of heat shock factor 1 promotes hepatic stellate cell activation and drives liver fibrosisen_US
dc.typeJournal Articleen_US
dspace.entity.typePublication
refterms.dateFOA2024-01-10T16:28:35Z
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