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dc.contributor.authorAmbade, Aditya
dc.contributor.authorCatalano, Donna
dc.contributor.authorLim, Arlene
dc.contributor.authorKopoyan, Andre
dc.contributor.authorShaffer, Scott A.
dc.contributor.authorMandrekar, Pranoti
dc.date2022-08-11T08:08:31.000
dc.date.accessioned2022-08-23T15:57:50Z
dc.date.available2022-08-23T15:57:50Z
dc.date.issued2014-10-01
dc.date.submitted2015-02-17
dc.identifier.citationJ Hepatol. 2014 Oct;61(4):903-11. doi: 10.1016/j.jhep.2014.05.024. Epub 2014 May 22. <a href="http://dx.doi.org/10.1016/j.jhep.2014.05.024">Link to article on publisher's site</a>
dc.identifier.issn0168-8278 (Linking)
dc.identifier.doi10.1016/j.jhep.2014.05.024
dc.identifier.pmid24859453
dc.identifier.urihttp://hdl.handle.net/20.500.14038/30294
dc.description.abstractBACKGROUND and AIMS: Heat shock protein 90 (hsp90) is an emerging therapeutic target in chronic liver diseases. Hsp90 plays an important role in liver immune cell activation; however its role in alcoholic liver disease (ALD) remains elusive. Here we hypothesize that hsp90 is crucial in alcohol induced steatosis and pro-inflammatory cytokine production. To test this hypothesis, we employed a pharmacological inhibitor of hsp90, 17-DMAG (17-Dimethylamino-ethylamino-17-demethoxygeldanamycin) in an in vivo mouse model of acute and chronic alcoholic liver injury. METHODS: C57BL/6 mice were given either a single dose of ethanol via oral gavage (acute) or chronically fed alcohol for 2 weeks followed by oral gavage (chronic-binge). 17-DMAG was administered during or at the end of feeding. Liver injury parameters, inflammatory cytokines and lipid metabolism genes were analysed. RESULTS: Our results reveal increased expression of hsp90 in human and mouse alcoholic livers. In vivo inhibition of hsp90, using 17-DMAG, not only prevented but also alleviated alcoholic liver injury, determined by lower serum ALT, AST and reduced hepatic triglycerides. Mechanistic analysis showed that 17-DMAG decreased alcohol mediated oxidative stress, reduced serum endotoxin, decreased inflammatory cells, and diminished sensitization of liver macrophages to LPS, resulting in downregulation of CD14, NFkappaB inhibition, and decreased pro-inflammatory cytokine production. Hsp90 inhibition decreased fatty acid synthesis genes via reduced nuclear SREBP-1 and favoured fatty acid oxidation genes via PPARalpha. CONCLUSIONS: Inhibition of hsp90 decreased alcohol induced steatosis and pro-inflammatory cytokines and inhibited alcoholic liver injury. Hsp90 is therefore relevant in human alcoholic cirrhosis and a promising therapeutic target in ALD. Elsevier B.V. All rights reserved.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=24859453&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1016/j.jhep.2014.05.024
dc.subjectBiochemistry
dc.subjectDigestive System Diseases
dc.subjectHepatology
dc.subjectPharmacology
dc.subjectTherapeutics
dc.titleInhibition of heat shock protein 90 alleviates steatosis and macrophage activation in murine alcoholic liver injury
dc.typeJournal Article
dc.source.journaltitleJournal of hepatology
dc.source.volume61
dc.source.issue4
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/555
dc.identifier.contextkey6675003
html.description.abstract<p>BACKGROUND and AIMS: Heat shock protein 90 (hsp90) is an emerging therapeutic target in chronic liver diseases. Hsp90 plays an important role in liver immune cell activation; however its role in alcoholic liver disease (ALD) remains elusive. Here we hypothesize that hsp90 is crucial in alcohol induced steatosis and pro-inflammatory cytokine production. To test this hypothesis, we employed a pharmacological inhibitor of hsp90, 17-DMAG (17-Dimethylamino-ethylamino-17-demethoxygeldanamycin) in an in vivo mouse model of acute and chronic alcoholic liver injury.</p> <p>METHODS: C57BL/6 mice were given either a single dose of ethanol via oral gavage (acute) or chronically fed alcohol for 2 weeks followed by oral gavage (chronic-binge). 17-DMAG was administered during or at the end of feeding. Liver injury parameters, inflammatory cytokines and lipid metabolism genes were analysed.</p> <p>RESULTS: Our results reveal increased expression of hsp90 in human and mouse alcoholic livers. In vivo inhibition of hsp90, using 17-DMAG, not only prevented but also alleviated alcoholic liver injury, determined by lower serum ALT, AST and reduced hepatic triglycerides. Mechanistic analysis showed that 17-DMAG decreased alcohol mediated oxidative stress, reduced serum endotoxin, decreased inflammatory cells, and diminished sensitization of liver macrophages to LPS, resulting in downregulation of CD14, NFkappaB inhibition, and decreased pro-inflammatory cytokine production. Hsp90 inhibition decreased fatty acid synthesis genes via reduced nuclear SREBP-1 and favoured fatty acid oxidation genes via PPARalpha.</p> <p>CONCLUSIONS: Inhibition of hsp90 decreased alcohol induced steatosis and pro-inflammatory cytokines and inhibited alcoholic liver injury. Hsp90 is therefore relevant in human alcoholic cirrhosis and a promising therapeutic target in ALD. Elsevier B.V. All rights reserved.</p>
dc.identifier.submissionpathfaculty_pubs/555
dc.contributor.departmentProteomics and Mass Spectrometry Facility
dc.contributor.departmentDepartment of Medicine, Division of Gastroenterology
dc.source.pages903-11


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