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

6533b7d7fe1ef96bd1268f16

RESEARCH PRODUCT

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

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

subject

medicine.medical_specialty Biopsy Gene Expression ADAM17 Protein Biology Amphiregulin Severity of Illness Index p38 Mitogen-Activated Protein Kinases digestive system Article Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Amphiregulin Growth factor receptor Non-alcoholic Fatty Liver Disease Internal medicine Hepatic Stellate Cells medicine Animals Humans Protein Kinase C PI3K/AKT/mTOR pathway Cell Proliferation 030304 developmental biology 0303 health sciences Multidisciplinary Fatty liver nutritional and metabolic diseases medicine.disease Fibrosis Actins digestive system diseases 3. Good health Enzyme Activation ErbB Receptors ADAM Proteins Disease Models Animal Endocrinology Hepatic stellate cell Cancer research 030211 gastroenterology & hepatology Tumor necrosis factor alpha Collagen Steatohepatitis Signal Transduction

description

AbstractAmphiregulin (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 be clinically useful anti-fibrotics in NAFLD.

year	journal	country	edition	language
2015-03-06	Scientific Reports

https://doi.org/10.1038/srep08812