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

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

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)


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
Pages (from-to)8812-
Number of pages10
JournalScientific Reports
Publication statusPublished - 2015

All Science Journal Classification (ASJC) codes

  • General


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