Differential TM4SF5-mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression

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dc.contributor.authorJ Ryu-
dc.contributor.authorE Kim-
dc.contributor.authorM K Kang-
dc.contributor.authorD G Song-
dc.contributor.authorE A Shin-
dc.contributor.authorH Lee-
dc.contributor.authorJ W Jung-
dc.contributor.authorS H Nam-
dc.contributor.authorJ E Kim-
dc.contributor.authorH J Kim-
dc.contributor.authorT Son-
dc.contributor.authorSemi Kim-
dc.contributor.authorH Y Kim-
dc.contributor.authorJ W Lee-
dc.date.accessioned2021-02-26T08:33:13Z-
dc.date.available2021-02-26T08:33:13Z-
dc.date.issued2021-
dc.identifier.issn00223417-
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/24138-
dc.description.abstractNonalcoholic fatty liver disease is a chronic condition involving steatosis, steatohepatitis and fibrosis, and its progression remains unclear. Although the tetraspanin transmembrane 4 L six family member 5 (TM4SF5) is involved in hepatic fibrosis and cancer, its role in nonalcoholic steatohepatitis (NASH) progression is unknown. We investigated the contribution of TM4SF5 to liver pathology using transgenic and KO mice, diet- or drug-treated mice, in vitro primary cells, and in human tissue. TM4SF5-overexpressing mice exhibited nonalcoholic steatosis and NASH in an age-dependent manner. Initially, TM4SF5-positive hepatocytes and liver tissue exhibited lipid accumulation, decreased Sirtuin 1 (SIRT1), increased sterol regulatory-element binding proteins (SREBPs) and inactive STAT3 via suppressor of cytokine signaling (SOCS)1/3 upregulation. In older mice, TM4SF5 promoted inflammatory factor induction, SIRT1 expression and STAT3 activity, but did not change SOCS or SREBP levels, leading to active STAT3-mediated ECM production for NASH progression. A TM4SF5-associated increase in chemokines promoted SIRT1 expression and progression to NASH with fibrosis. Suppression of the chemokine CCL20 reduced immune cell infiltration and ECM production. Liver tissue from high-fat diet- or CCl4-treated mice and human patients exhibited TM4SF5-dependent steatotic or steatohepatitic livers with links between TM4SF5-mediated SIRT1 modulation and SREBP or SOCS/STAT3 signaling axes. TM4SF5-mediated STAT3 activation in fibrotic NASH livers increased collagen I and laminin γ2. Both collagen I α1 and laminin γ2 suppression resulted in reduced SIRT1 and active STAT3, but no change in SREBP1 or SOCS, and abolished CCl4?mediated mouse liver damage. TM4SF5-mediated signaling pathways that involve SIRT1, SREBPs and SOCS/STAT3 promoted progression to NASH. Therefore, TM4SF5 and its downstream effectors may be promising therapeutic targets to treat nonalcoholic fatty liver disease.-
dc.publisherWiley-
dc.titleDifferential TM4SF5-mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression-
dc.title.alternativeDifferential TM4SF5-mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression-
dc.typeArticle-
dc.citation.titleJournal of Pathology-
dc.citation.number0-
dc.citation.endPage67-
dc.citation.startPage55-
dc.citation.volume253-
dc.contributor.affiliatedAuthorSemi Kim-
dc.contributor.alternativeName류지혜-
dc.contributor.alternativeName김은미-
dc.contributor.alternativeName강민경-
dc.contributor.alternativeName송대근-
dc.contributor.alternativeName신은애-
dc.contributor.alternativeName이해송-
dc.contributor.alternativeName정재우-
dc.contributor.alternativeName남세희-
dc.contributor.alternativeName김지언-
dc.contributor.alternativeName김혜진-
dc.contributor.alternativeName손태권-
dc.contributor.alternativeName김세미-
dc.contributor.alternativeName김휘영-
dc.contributor.alternativeName이정원-
dc.identifier.bibliographicCitationJournal of Pathology, vol. 253, pp. 55-67-
dc.identifier.doi10.1002/path.5548-
dc.subject.keywordCCL20-
dc.subject.keywordLaminin γ2-
dc.subject.keywordNAFLD-
dc.subject.keywordNASH-
dc.subject.keywordSignal transduction-
dc.subject.keywordSIRT1-
dc.subject.keywordSOCS-
dc.subject.keywordSREBP-
dc.subject.keywordSTAT3-
dc.subject.keywordTM4SF5-
dc.subject.localCCL20-
dc.subject.localNAFLD-
dc.subject.localNASH-
dc.subject.localSignal transduction-
dc.subject.localSIRT1-
dc.subject.localSIRT-1-
dc.subject.localSREBP-
dc.subject.localSTAT3-
dc.subject.localTM4SF5-
dc.description.journalClassY-
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Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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