title: Adiponectin reduces hepatic stellate cell migration by promoting tissue inhibitor of metalloproteinase-1 (TIMP-1) secretion.
abstract: Hepatic stellate cells (HSC) are central players in liver fibrosis that when activated, proliferate, migrate to sites of liver injury, and secrete extracellular matrix. Obesity, a known risk factor for liver fibrosis is associated with reduced levels of adiponectin, a protein that inhibits liver fibrosis in vivo and limits HSC proliferation and migration in vitro. Adiponectin-mediated activation of adenosine monophosphate-activated kinase (AMPK) inhibits HSC proliferation, but the mechanism by which it limits HSC migration to sites of injury is unknown. Here we sought to elucidate how adiponectin regulates HSC motility. Primary rat HSCs were isolated and treated with adiponectin in migration assays. The in vivo actions of adiponectin were examined by treating mice with carbon tetrachloride for 12 weeks and then injecting them with adiponectin. Cell and tissue samples were collected and analyzed for gene expression, signaling, and histology. Serum from patients with liver fibrosis was examined for adiponectin and tissue inhibitor of metalloproteinase-1 (TIMP-1) protein. Adiponectin administration into mice increased TIMP-1 gene and protein expression. In cultured HSCs, adiponectin promoted TIMP-1 expression and through binding of TIMP-1 to the CD63/β1-integrin complex reduced phosphorylation of focal adhesion kinase to limit HSC migration. In mice with liver fibrosis, adiponectin had similar effects and limited focal adhesion kinase phosphorylation. Finally, in patients with advanced fibrosis, there was a positive correlation between serum adiponectin and TIMP-1 levels. In sum, these data show that adiponectin stimulates TIMP-1 secretion by HSCs to retard their migration and contributes to the anti-fibrotic effects of adiponectin.
authors.affiliation: From the Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia and.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ramezani-Moghadam
authors.affiliation: From the Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia and.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia and.
authors.forename: Vikki
authors.initials: V
authors.lastname: Ho
authors.affiliation: From the Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia and.
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Iseli
authors.affiliation: From the Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia and.
authors.forename: Badr
authors.initials: B
authors.lastname: Alzahrani
authors.affiliation: the Department of Medicine, the University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: From the Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia and.
authors.forename: David
authors.initials: D
authors.lastname: Van der Poorten
authors.affiliation: From the Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia and.
authors.forename: Liang
authors.initials: L
authors.lastname: Qiao
authors.affiliation: From the Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia and.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.affiliation: From the Storr Liver Centre, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia and lionel.hebbard@sydney.edu.au.
authors.forename: Lionel
authors.initials: L
authors.lastname: Hebbard
mesh_terms: D052242:Adiponectin / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060149:Tetraspanin 30 / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D052242:Adiponectin; D019012:Integrin beta1; D060149:Tetraspanin 30; D019715:Tissue Inhibitor of Metalloproteinase-1; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: Adiponectin; Fibrosis; Liver; Tetraspanin; Tissue Inhibitor of Metalloproteinase (TIMP)