Received for publication January 17, 2008.
Revised March 6, 2008.
Accepted for publication March 12, 2008.

New role of resistin in lipopolysaccharide-induced liver damage in mice

Abstract

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. The purpose of the present study was to therefore 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. Whereas having no effect alone, resistin significantly enhanced hepatic inflammation and necrosis caused by LPS. Resistin increased expression of proinflammatory genes (e.g., PAI-1) and activity of MAP kinase (ERK1/2) 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), 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 appears to involve, at least in part, upregulation 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.

Key words: FIZZ3, PAI-1, fibrin deposition, hemostasis, inflammation, insulin resistance