Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis.
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 be clinically useful anti-fibrotics in NAFLD.
Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
Chad
C
McKee
Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
Barbara
B
Sigala
Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
Junpei
J
Soeda
Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
Angelina
A
Mouralidarane
Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
Maelle
M
Morgan
Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", S. Giovanni Rotondo (FG), Italy.
Gianluigi
G
Mazzoccoli
1] Dipartimento di Scienze Giuridiche della Società e dello Sport, Università degli Studi di Palermo, Palermo, Italy [2] Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Università degli Studi di Palermo, Palermo, Italy.
Francesca
F
Rappa
1] Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Università degli Studi di Palermo, Palermo, Italy [2] Istituto Euro-Mediterraneo di Scienza e Tecnologia (IEMEST), Palermo, Italy.
Francesco
F
Cappello
Dipartimento di Patologia, University of Palermo, Italy.
Daniela
D
Cabibi
Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza", S. Giovanni Rotondo (FG), Italy.
Valerio
V
Pazienza
Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
Claire
C
Selden
Department of Pathology, Laboratory of Morphology and Molecular Pathology, University Hospitals of Leuven, Leuven, Belgium.
Tania
T
Roskams
1] Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK [2] Istituto Euro-Mediterraneo di Scienza e Tecnologia (IEMEST), Palermo, Italy [3] Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza", S. Giovanni Rotondo (FG), Italy.
Manlio
M
Vinciguerra
Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
Jude A
JA
Oben
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000199:Actins / Q000235:genetics / Q000378:metabolism; D066258:Amphiregulin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001706:Biopsy; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000199:Actins; D066258:Amphiregulin; C544013:alpha-smooth muscle actin, mouse; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse