Background: Adiponectin was suggested to exert hepatoprotective effects in animal models of tetrachlorcarbonate-, endotoxin- and alcohol-induced liver injury. Further, in patients with non-alcoholic fatty liver disease (NAFLD) low adiponectin levels were found to be associated with more severe steatosis and hepatic inflammation.
Methods: To investigate the molecular basis of the hepatoprotective effects of adiponectin primary human hepatocytes were incubated with recombinant adiponectin for 24 h. GeneChip analysis was performed and CXCL8 mRNA was found induced.
Results: Adiponectin upregulated CXCL8 mRNA and induced CXCL8 secretion in primary human hepatocytes. Elevated CXCL8 in the supernatants was measured as early as 3 h after the addition of adiponectin to the hepatocytes. Adiponectin receptor 1 and 2 are expressed in hepatocytes and knock-down of AdipoR1, but not AdipoR2, by siRNA abrogated adiponectin induced CXCL8 release. The p38 MAPK inhibitor SB203580 did not significantly diminish adiponectin-mediated release of CXCL8. Electrophoretic mobility shift assays (EMSAs) revealed that adiponectin activated NFκB in primary hepatocytes but not in HepG2 cells. The hepatocytic cell lines HepG2, Hep3B and PLC were also incubated with adiponectin but CXCL8 release was not significantly induced in these cell lines.
Conclusions: The current experiments revealed that adiponectin activated NFkappaB and induced CXCL8 in primary human hepatocytes whereas hepatocytic cell lines were resistant to the effects of adiponectin. So far the role of CXCL8 in hepatic injury is not clearly established. Whereas CXCL8-mediated recruitment of neutrophils may be harmful to the liver, CXCL8 was also described to protect the liver against galactosamine/endotoxin and T-cell mediated apoptosis.
03 - 07 May 2008
European Society of Endocrinology