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Critical role of CREBH‐mediated induction of transforming growth factor β2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells

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‐regulation of transforming growth factor β (TGF‐β), especially TGF‐β2, which is mediated by activation of liver‐enriched transcription factor cAMP‐responsive element‐binding protein, hepatocyte specific (CREBH) triggered by HCV infection and its functional significance for induction of profibrogenic phenotypes by interaction of HCV‐infected cells with hepatic stellate cells (HSCs). Compared to TGF‐β1, expression of TGF‐β2 mRNA was induced faster and to a higher level upon HCV infection. Serum TGF‐β2 levels in hepatitis C patients were higher compared to those in healthy individuals and were positively correlated with hepatic fibrosis stages F0‐F2. TGF‐β2 promoter activity was decreased and increased, respectively, by silencing and overexpression of CREBH. CREBH recognition sites were identified in the TGF‐β2 promoter. CREBH binding to the promoter and its increase in cells expressing HCV Core‐NS2 were shown by gel mobility shift and chromatin immunoprecipitation, respectively. The active form of CREBH was detectable in HCV‐infected chimeric mice with human livers and cells expressing HCV proteins. Involvement of CREBH in HCV‐induced fibrogenic response was further demonstrated in the CREBH null‐mutant mouse model. Fibrogenic phenotypes were assessed using co‐cultures of HCV‐infected cells and HSCs. Expressions of fibrogenic factors and TGF‐β1 increasing in the co‐cultures was prevented by TGF‐β2‐ or CREBH silencing. Conclusion: CREBH was identified as a key positive regulator of TGF‐β2 transcription in HCV‐infected cells. TGF‐β2 released from infected cells potentially contributes to cross‐induction of TGF‐β in an autocrine manner through its own signaling pathway, leading to an increase in fibrogenic responses in adjacent HSCs. (Hepatology 2017;66:1430–1443).