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In this study, we examined the potential role of GSTA<\/jats:styled-content>4 on protein carbonylation and progression of alcoholic liver disease by examining the development of liver injury in male wild\u2010type (WT) SV\/J mice and SV<\/jats:styled-content>\/J mice lacking functional GSTA<\/jats:styled-content>4 (GSTA<\/jats:styled-content>4\u2212\/\u2212<\/jats:sup> mice).<\/jats:p><\/jats:sec>Methods<\/jats:title>Adult male WT<\/jats:styled-content> and GSTA<\/jats:styled-content>4\u2212\/\u2212<\/jats:sup> mice were fed chow (N<\/jats:italic>\u00a0=\u00a010 to 12) or high\u2010fat Lieber\u2010DeCarli liquid diets containing up to 28% calories as ethanol (EtOH) (N<\/jats:italic>\u00a0=\u00a018 to 20) for 116\u00a0days. At the end of the study, half of the EtOH\u2010fed mice were acutely challenged with an EtOH binge (3\u00a0g\/kg given intragastrically) 12\u00a0hours before sacrifice. Carbonylation of liver proteins was assessed by immunohistochemical staining for 4\u2010HNE<\/jats:styled-content> adduction and by comprehensive liquid chromatography\u2013tandem mass spectrometry (LC<\/jats:styled-content>\u2010MS<\/jats:styled-content>\/MS<\/jats:styled-content>) of purified carbonylated proteins.<\/jats:p><\/jats:sec>Results<\/jats:title>Chronic EtOH<\/jats:styled-content> intake significantly increased hepatic 4\u2010HNE<\/jats:styled-content> adduction and protein carbonylation, including carbonylation of ribosomal proteins. EtOH<\/jats:styled-content> intake also resulted in steatosis and increased serum alanine aminotransferase. Hepatic infiltration with B cells, T cells, and neutrophils and mRNA<\/jats:styled-content> expression of pro\u2010inflammatory cytokines tumor necrosis factor (TNF)\u03b1<\/jats:italic> and interferon (IFN)\u03b3<\/jats:italic> was modest in WT<\/jats:styled-content> mice. However, an EtOH binge increased hepatic necrosis, hepatic cell proliferation, and expression of TNF<\/jats:styled-content>\u03b1 <\/jats:italic>mRNA<\/jats:styled-content> (p<\/jats:italic>\u00a0<\u00a00.05). EtOH<\/jats:styled-content> treatment of GSTA<\/jats:styled-content>4\u2212\/\u2212<\/jats:sup> mice increased B\u2010cell infiltration and increased mRNA<\/jats:styled-content> expression of TNF<\/jats:styled-content>\u03b1<\/jats:italic> and IFN<\/jats:styled-content>\u03b3<\/jats:italic> and of matrix remodeling markers MMP<\/jats:styled-content>9, MMP<\/jats:styled-content>13, and Col<\/jats:styled-content>1A1 (p<\/jats:italic>\u00a0<\u00a00.05). GSTA<\/jats:styled-content>4\u2212\/\u2212<\/jats:sup> mice exhibited panlobular rather than periportal distribution of 4\u2010HNE<\/jats:styled-content>\u2010adducted proteins and increased overall 4\u2010HNE<\/jats:styled-content> staining after EtOH<\/jats:styled-content> binge. Comprehensive LC\u2010MS of carbonylated proteins identified 1,022 proteins of which 189 were unique to the GSTA<\/jats:styled-content>4\u2212\/\u2212<\/jats:sup> group.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>These data suggest long\u2010term adaptation to EtOH<\/jats:styled-content> in WT<\/jats:styled-content> mice does not occur in GSTA<\/jats:styled-content>4\u2212\/\u2212<\/jats:sup> mice. Products of lipid peroxidation appear to play a role in inflammatory responses due to EtOH<\/jats:styled-content>. And EtOH<\/jats:styled-content> effects on B\u2010cell infiltration and autoimmune responses may be secondary to formation of carbonyl adducts.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.13766","type":"journal-article","created":{"date-parts":[[2018,4,30]],"date-time":"2018-04-30T13:18:10Z","timestamp":1525094290000},"page":"1192-1205","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Knockout of the Gsta4<\/i> Gene in Male Mice Leads to an Altered Pattern of Hepatic Protein Carbonylation and Enhanced Inflammation Following Chronic Consumption of an Ethanol Diet"],"prefix":"10.1111","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9618-9885","authenticated-orcid":false,"given":"Colin T.","family":"Shearn","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences School of Pharmacy University of Colorado Anschutz Medical Campus Aurora Colorado"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casey F.","family":"Pulliam","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics Louisiana State University Health Sciences Center New Orleans Louisiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics Louisiana State University Health Sciences Center New Orleans Louisiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle","family":"Meredith","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics Louisiana State University Health Sciences Center New Orleans Louisiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly E.","family":"Mercer","sequence":"additional","affiliation":[{"name":"Arkansas Children's Nutrition Center University of Arkansas for Medical Sciences Little Rock Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura M.","family":"Saba","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences School of Pharmacy University of Colorado Anschutz Medical Campus Aurora Colorado"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Orlicky","sequence":"additional","affiliation":[{"name":"Department of Pathology School of Medicine University of Colorado Anschutz Medical Center Aurora Colorado"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin J.","family":"Ronis","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics Louisiana State University Health Sciences Center New Orleans Louisiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis R.","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of 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