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dc.contributor.authorShearn, Colin T.
dc.contributor.authorAnderson, Aimee L.
dc.contributor.authorMiller, Colin G.
dc.contributor.authorNoyd, Reed C.
dc.contributor.authorDevereaux, Michael W.
dc.contributor.authorBalasubramaniyan, Nata
dc.contributor.authorOrlicky, David J.
dc.contributor.authorSchmidt, Edward E.
dc.contributor.authorSokol, Ronald J.
dc.date.accessioned2023-02-23T15:29:11Z
dc.date.available2023-02-23T15:29:11Z
dc.date.issued2023-01
dc.identifier.issn2471-254X
dc.identifier.urihttps://scholarworks.montana.edu/xmlui/handle/1/17723
dc.description.abstractBackground and Aims: Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by periportal inflammation with progression to hepatic fibrosis and ultimately cirrhosis. We recently reported that the thioredoxin antioxidant response is dysregulated during primary sclerosing cholangitis. The objective of this study was to examine the impact of genetic and pharmacological targeting of thioredoxin reductase 1 (TrxR1) on hepatic inflammation and liver injury during acute cholestatic injury. Approach and Results: Primary mouse hepatocytes and intrahepatic macrophages were isolated from 3-day bile duct ligated (BDL) mice and controls. Using wildtype and mice with a liver-specific deletion of TrxR1 (TrxR1LKO), we analyzed the effect of inhibition or ablation of TrxR1 signaling on liver injury and inflammation. Immunohistochemical analysis of livers from BDL mice and human cholestatic patients revealed increased TrxR1 staining in periportal macrophages and hepatocytes surrounding fibrosis. qPCR analysis of primary hepatocytes and intrahepatic macrophages revealed increased TrxR1 mRNA expression following BDL. Compared with sham controls, BDL mice exhibited increased inflammation, necrosis, and increased mRNA expression of pro-inflammatory cytokines, fibrogenesis, the NLRP3 inflammatory complex, and increased activation of NFkB, all of which were ameliorated in TrxR1LKO mice. Importantly, following BDL, TrxR1LKO induced periportal hepatocyte expression of Nrf2-dependent antioxidant proteins and increased mRNA expression of basolateral bile acid transporters with reduced expression of bile acid synthesis genes. In the acute BDL model, the TrxR1 inhibitor auranofin (10 mg/kg/1 d preincubation, 3 d BDL) ameliorated BDL-dependent increases in Nlrp3, GsdmD, Il1β, and TNFα mRNA expression despite increasing serum alanine aminotransferase, aspartate aminotransferase, bile acids, and bilirubin. Conclusions: These data implicate TrxR1-signaling as an important regulator of inflammation and bile acid homeostasis in cholestatic liver injury.en_US
dc.language.isoen_USen_US
dc.publisherOvid Technologiesen_US
dc.rightscc-byen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectthioredoxinen_US
dc.subjecthepatic inflammationen_US
dc.subjectmacrophage activationen_US
dc.titleThioredoxin reductase 1 regulates hepatic inflammation and macrophage activation during acute cholestatic liver injuryen_US
dc.typeArticleen_US
mus.citation.extentfirstpage1en_US
mus.citation.extentlastpage16en_US
mus.citation.issue1en_US
mus.citation.journaltitleHepatology Communicationsen_US
mus.citation.volume7en_US
mus.identifier.doi10.1097/HC9.0000000000000020en_US
mus.relation.collegeCollege of Agricultureen_US
mus.relation.departmentMicrobiology & Immunology.en_US
mus.relation.universityMontana State University - Bozemanen_US
mus.data.thumbpage5en_US


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