Adiponectin Reduces Hepatic Stellate Cell Migration by Promoting Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Secretion

• Published in: The Journal of biological chemistry 2015-02, Vol.290 (9), p.5533-5542
• Main Authors: Ramezani-Moghadam, Mehdi, Wang, Jianhua, Ho, Vikki, Iseli, Tristan J., Alzahrani, Badr, Xu, Aimin, Van der Poorten, David, Qiao, Liang, George, Jacob, Hebbard, Lionel
• Format: Article
• Language: English
• Subjects: Adiponectin; Adiponectin - blood; Adiponectin - pharmacology; Animals; Apoptosis - drug effects; Blotting, Western; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Fibrosis; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Gene Expression - drug effects; Hepatic Stellate Cells - cytology; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Humans; Integrin beta1 - genetics; Integrin beta1 - metabolism; Liver; Male; Mice, Inbred C57BL; Microscopy, Confocal; Molecular Bases of Disease; Non-alcoholic Fatty Liver Disease - blood; Phosphorylation - drug effects; Protein Binding - drug effects; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Tetraspanin; Tetraspanin 30 - genetics; Tetraspanin 30 - metabolism; Tissue Inhibitor of Metalloproteinase (TIMP); Tissue Inhibitor of Metalloproteinase-1 - blood; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.598011

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. Adiponectin has been shown to limit liver fibrosis, but the molecular mechanisms remain unknown. In vitro and in vivo adiponectin increases TIMP-1 secretion, which binds to the CD63/β1-integrin complex to decrease FAK activity and stellate cell migration. Adiponectin-promoted TIMP-1 plays an important role in limiting liver fibrosis. Targeting adiponectin signaling could be a useful way to limit liver fibrosis.