{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T05:38:04Z","timestamp":1771047484770,"version":"3.50.1"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2017,9,29]],"date-time":"2017-09-29T00:00:00Z","timestamp":1506643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2017,9,29]],"date-time":"2017-09-29T00:00:00Z","timestamp":1506643200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:p>Mechanisms of hepatic fibrogenesis induced by hepatitis C virus (HCV), one of the leading causes of liver fibrosis, are not fully understood. We studied transcriptional up\u2010regulation of transforming growth factor \u03b2 (TGF\u2010\u03b2), especially TGF\u2010\u03b22, which is mediated by activation of liver\u2010enriched transcription factor cAMP\u2010responsive element\u2010binding protein, hepatocyte specific (CREBH) triggered by HCV infection and its functional significance for induction of profibrogenic phenotypes by interaction of HCV\u2010infected cells with hepatic stellate cells (HSCs). Compared to TGF\u2010\u03b21, expression of TGF\u2010\u03b22 mRNA was induced faster and to a higher level upon HCV infection. Serum TGF\u2010\u03b22 levels in hepatitis C patients were higher compared to those in healthy individuals and were positively correlated with hepatic fibrosis stages F0\u2010F2. TGF\u2010\u03b22 promoter activity was decreased and increased, respectively, by silencing and overexpression of CREBH. CREBH recognition sites were identified in the TGF\u2010\u03b22 promoter. CREBH binding to the promoter and its increase in cells expressing HCV Core\u2010NS2 were shown by gel mobility shift and chromatin immunoprecipitation, respectively. The active form of CREBH was detectable in HCV\u2010infected chimeric mice with human livers and cells expressing HCV proteins. Involvement of CREBH in HCV\u2010induced fibrogenic response was further demonstrated in the CREBH null\u2010mutant mouse model. Fibrogenic phenotypes were assessed using co\u2010cultures of HCV\u2010infected cells and HSCs. Expressions of fibrogenic factors and TGF\u2010\u03b21 increasing in the co\u2010cultures was prevented by TGF\u2010\u03b22\u2010 or CREBH silencing. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: CREBH was identified as a key positive regulator of TGF\u2010\u03b22 transcription in HCV\u2010infected cells. TGF\u2010\u03b22 released from infected cells potentially contributes to cross\u2010induction of TGF\u2010\u03b2 in an autocrine manner through its own signaling pathway, leading to an increase in fibrogenic responses in adjacent HSCs. (H<jats:sc>epatology<\/jats:sc> 2017;66:1430\u20131443).<\/jats:p>","DOI":"10.1002\/hep.29319","type":"journal-article","created":{"date-parts":[[2017,6,16]],"date-time":"2017-06-16T10:26:34Z","timestamp":1497608794000},"page":"1430-1443","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":31,"title":["Critical role of CREBH\u2010mediated induction of transforming growth factor \u03b22 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells"],"prefix":"10.1097","volume":"66","author":[{"given":"Takeshi","family":"Chida","sequence":"first","affiliation":[{"name":"Department of Virology & Parasitology,Laboratory Animal Facilites & Services, Hamamatsu University School of Medicine,Hamamatsu,Japan"},{"name":"2nd Department of Internal Medicine, Laboratory Animal Facilites & Services,Hamamatsu University School of Medicine,Hamamatsu,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7020-7312","authenticated-orcid":false,"given":"Masahiko","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Virology & Parasitology,Laboratory Animal Facilites & Services, Hamamatsu University School of Medicine,Hamamatsu,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Department of Virology & Parasitology,Laboratory Animal Facilites & Services, Hamamatsu University School of Medicine,Hamamatsu,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumi","family":"Kanegae","sequence":"additional","affiliation":[{"name":"Core Research Facilities of Basic Science (Molecular Genetics),Research Center for Medical 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Medicine,Hamamatsu,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshimi","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine,University of Tsukuba,Tsukuba,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases,Osaka University,Osaka,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitoshi","family":"Shimano","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine,University of Tsukuba,Tsukuba,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomokazu","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine,The Jikei University School of Medicine,Tokyo,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshimasa","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"2nd Department of Internal Medicine, Laboratory Animal Facilites & Services,Hamamatsu University School of Medicine,Hamamatsu,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takafumi","family":"Suda","sequence":"additional","affiliation":[{"name":"2nd Department of Internal Medicine, Laboratory Animal Facilites & Services,Hamamatsu University School of Medicine,Hamamatsu,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuro","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Virology & Parasitology,Laboratory Animal Facilites & Services, Hamamatsu University School of 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