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. 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 ϩ 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.Hepatic disease (e.g., nonalcoholic steatohepatitis) is a common complication of insulin resistance and type II diabetes and is mediated, at least in part, by enhanced systemic and local inflammation (Hotamisligil et al., 1993). Inflammation during insulin resistance has often correlated with overproduction of local proinflammatory cytokines, such as TNF␣ (Lehrke et al., 2004). Furthermore, recent work has indicated that some adipokines, whose release from adipose tissue is altered during insulin resistance (i.e., leptin and adiponectin), also directly coordinate the local inflammatory response in liver (Tsochatzis et al., 2006). However, mechanisms by which adipokines modulate hepatic inflammation and the possible role of other adipokines in this process are unclear.Resistin, also known as FIZZ3 and adipocyte-derived secretory factor (Holcomb et al., 2000;Steppan et al., 2001b;Rajala et al., 2002), is a 12.5-kDa polypeptide synthesized and secreted by adipocytes. In rodents, serum levels of resistin were elevated in models of obesity, and high-dose resistin altered glucose metabolism through impairment of insulin action, particularly in the live...

Adipokines and Redox Signaling: Impact on Fatty Liver Disease

“…In humans, resistin is expressed within the liver during severe damage, including the one associated with NASH, and correlates with infiltration of inflammatory cells (22). In rats, resistin administration significantly worsens inflammation after LPS injection, through the involvement of the coagulation cascade (16). In addition, in a model of cirrhosis, higher gene and protein expression of resistin and TNF-a was observed in epididymal fat, and TNF injection upregulated resistin (107).…”

“…In rats, resistin administration significantly worsens inflammation induced by LPS injection (16). In humans, resistin is expressed within the liver during severe damage, including the one associated with NASH, and correlates with infiltration of inflammatory cells (22).…”

The effects of ovariectomy and LPS-induced endotoxemia on resistin levels in female rats

“…In addition, resistin might be involved in the inflammatory response in humans and rodents. In rodents, the concentration of resistin mRNA in white adipose tissue (WAT) is increased by lipopolysaccharide (LPS) both in vivo and in vitro [4], and the co-administration of resistin increases the LPS-induced reaction of hepatic pro-inflammatory cytokines [5]. Similarly, the serum resistin level is increased under septic conditions and is associated with the severity of sepsis and the degree of the inflammatory response in humans [6].…”

Extracellular matrix proteins and the liver-lung axis in disease.

“…Specifically, the Roman lab has shown that chronic alcohol exposure increases pulmonary fibronectin deposition via alterations in both expression and degradation of ECM components (68). Similarly, our lab has shown that ethanol enhances increased hepatic fibrin deposition caused by LPS and that subsequent inflammatory damage to the liver is a direct effect of fibrin accumulation (29,50,(69)(70)(71).…”

“…Immunofluorescent detection of fibrin deposition was performed as described in (69). Briefly, frozen liver sections (6 μm thick) were fixed in 10% buffered formalin containing 2% acetic acid to solubilize all but cross-linked fibrin.…”