title: MMP-9 activity is increased by adiponectin in primary human hepatocytes but even negatively correlates with serum adiponectin in a rodent model of non-alcoholic steatohepatitis.
abstract: Adiponectin protects from inflammation and fibrosis in metabolic liver disease. In the present study we analyzed whether this adipokine may directly affect the activity of matrix metalloproteinases (MMPs), central regulators of fibrinolysis, in hepatocytes. Global gene expression analysis indicated upregulation of MMP-9 and tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in primary human hepatocytes (PHH) in response to stimulation with adiponectin, and these results were confirmed by real-time RT-PCR. Furthermore, gelatin zymography revealed that MMP-9 activity was significantly induced in supernatants of adiponectin stimulated PHHs. In a murine model of hepatic steatosis and in human steatotic liver samples hepatic MMP-9 activity was not significantly altered. However, in two different murine models of non-alcoholic steatohepatitis (NASH) MMP-9 activity was significantly elevated compared to chow fed control mice. Of note, MMP-9 activity did not or even negatively, respectively, correlate with adiponectin serum levels in these models. The current data indicate that in NASH hepatic inflammation and fibrosis but not hepatic steatosis induce liver MMP-9 activity, and this induction seems to be related to the anti-inflammatory activity of adiponectin rather than its effect on hepatocellular MMP-9 expression.
authors.affiliation: Department of Internal Medicine I, Regensburg University Hospital, D-93042 Regensburg, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Wanninger
authors.forename: Roland
authors.initials: R
authors.lastname: Walter
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bauer
authors.forename: Kristina
authors.initials: K
authors.lastname: Eisinger
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäffler
authors.forename: Christoph
authors.initials: C
authors.lastname: Dorn
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.forename: Christa
authors.initials: C
authors.lastname: Buechler
mesh_terms: D052242:Adiponectin / Q000097:blood* / Q000494:pharmacology; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000097:blood* / Q000201:enzymology* / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1