PT - JOURNAL ARTICLE AU - Juliane I. Beier AU - Luping Guo AU - Claudia von Montfort AU - J. Phillip Kaiser AU - Swati Joshi-Barve AU - Gavin E. Arteel TI - New Role of Resistin in Lipopolysaccharide-Induced Liver Damage in Mice AID - 10.1124/jpet.108.136721 DP - 2008 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 801--808 VI - 325 IP - 3 4099 - http://jpet.aspetjournals.org/content/325/3/801.short 4100 - http://jpet.aspetjournals.org/content/325/3/801.full SO - J Pharmacol Exp Ther2008 Jun 01; 325 AB - Studies in rodents suggest that the adipocytokine resistin causes insulin resistance via impairing normal insulin signaling. However, in humans, resistin may play a more important role in inflammation than in insulin resistance. Whether resistin contributes to inflammation in rodents is unclear. Therefore, the purpose of the present study was to determine the effect of resistin exposure on the basal and stimulated [lipopolysaccharide (LPS)] inflammatory response in mouse liver in vivo. Resistin alone had no major effects on hepatic expression of insulin-responsive genes, either in the presence or absence of LPS. Although it had no effect alone, resistin significantly enhanced hepatic inflammation and necrosis caused by LPS. Resistin increased expression of proinflammatory genes, e.g., plasminogen activator inhibitor (PAI)-1, and activity of mitogen-activated protein (MAP) kinase, extracellular signal-regulated kinase 1/2, caused by LPS, but had little effect on anti-inflammatory gene expression. Resistin also enhanced fibrin deposition (an index of hemostasis) caused by LPS. The increase in PAI-1 expression, fibrin deposition, and liver damage caused by LPS + resistin was almost completely prevented either by inhibiting the coagulation cascade, hirudin, or by blocking MAP kinase signaling, U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio) butadiene], indicating that these pathways play a causal role in observed enhanced liver damage caused by resistin. Taken together, the augmentation of LPS-induced liver damage caused by resistin seems to involve, at least in part, up-regulation of hepatic inflammation via mechanisms most likely involving the coagulation cascade and fibrin accumulation. These data also suggest that resistin may have proinflammatory roles in mouse liver independent of its effects on insulin signaling, analogous to previous work in humans. The American Society for Pharmacology and Experimental Therapeutics