Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis

Chad McKee, Barbara Sigala, Junpei Soeda, Angelina Mouralidarane, Maelle Morgan, Gianluigi Mazzoccoli, Francesca Rappa, Francesco Cappello, Daniela Cabibi, Valerio Pazienza, Claire Selden, Tania Roskams, Manlio Vinciguerra, Jude A. Oben

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Abstract

Amphiregulin (AR) involvement in liver fibrogenesis and hepatic stellate cells (HSC) regulation is under study. Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular cancer (HCC). Our aim was to investigate ex vivo the effect of AR on human primary HSC (hHSC) and verify in vivo the relevance of AR in NAFLD fibrogenesis. hHSC isolated from healthy liver segments were analyzed for expression of AR and its activator, TNF- converting enzyme (TACE). AR induction of hHSC proliferation and matrix production was estimated in the presence of antagonists. AR involvement in fibrogenesis was also assessed in a mouse model of NASH and in humans with NASH. hHSC time dependently expressed AR and TACE. AR increased hHSC proliferation through several mitogenic signaling pathways such as EGFR, PI3K and p38. AR also induced marked upregulation of hHSC fibrogenic markers and reduced hHSC death. AR expression was enhanced in the HSC of a murine model of NASH and of severe human NASH. In conclusion, AR induces hHSC fibrogenic activity via multiple mitogenic signaling pathways, and is upregulated in murine and human NASH, suggesting that AR antagonists may be clinically useful anti-fibrotics in NAFLD.

Original languageEnglish
Article number8812
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 2015

ASJC Scopus subject areas

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    McKee, C., Sigala, B., Soeda, J., Mouralidarane, A., Morgan, M., Mazzoccoli, G., Rappa, F., Cappello, F., Cabibi, D., Pazienza, V., Selden, C., Roskams, T., Vinciguerra, M., & Oben, J. A. (2015). Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis. Scientific Reports, 5, [8812]. https://doi.org/10.1038/srep08812