RT Journal Article
SR Electronic
T1 New Role of Resistin in Lipopolysaccharide-Induced Liver Damage in Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 801
OP 808
DO 10.1124/jpet.108.136721
VO 325
IS 3
A1 Juliane I. Beier
A1 Luping Guo
A1 Claudia von Montfort
A1 J. Phillip Kaiser
A1 Swati Joshi-Barve
A1 Gavin E. Arteel
YR 2008
UL http://jpet.aspetjournals.org/content/325/3/801.abstract
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