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

Scientific Reports
Chad McKeeJude A Oben

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-α 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...Continue Reading

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Citations

Jan 6, 2016·International Journal of Molecular Sciences·Karin Komposch, Maria Sibilia
Jun 17, 2015·Clinical and Experimental Medicine·Gianluigi MazzoccoliFabio Marra
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Jun 3, 2020·Nature Reviews. Gastroenterology & Hepatology·Prakash RamachandranNeil C Henderson
May 1, 2021·International Journal of Molecular Sciences·Maria NotarnicolaCaterina Messa
Jul 1, 2021·Biological Chemistry·Mazin Al-SalihiPhilipp A Lang
Jul 8, 2021·Cell Reports·Diogo Paramos-de-CarvalhoLeonor Saúde

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Methods Mentioned

BETA
flow cytometry
biopsies
biopsy
confocal microscopy
PCR
electrophoresis
Assay

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