New role of resistin in lipopolysaccharide-induced liver damage in mice
New role of resistin in lipopolysaccharide-induced liver damage in mice
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DOI：
10.1124/jpet.108.136721
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发表时间：
2008-06-01
影响因子：
3.5
通讯作者：
Arteel, Gavin E.
中科院分区：
文献类型：
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作者：
Beier, Juliane I.;Guo, Luping;Arteel, Gavin E.
对啮齿动物的研究表明，脂肪细胞因子抵抗素通过损害正常的胰岛素信号传导而导致胰岛素抵抗。然而，在人类中，抵抗素在炎症中发挥的作用可能比在胰岛素抵抗中发挥的作用更重要。抵抗素是否会导致啮齿类动物的炎症尚不清楚。因此，本研究的目的是确定抵抗素暴露对体内小鼠肝脏基础和刺激的[脂多糖（LPS）]炎症反应的影响。无论是否存在 LPS，单独的抵抗素对胰岛素反应基因的肝脏表达没有重大影响。虽然抵抗素单独没有作用，但它显着增强了 LPS 引起的肝脏炎症和坏死。抵抗素增加促炎基因的表达，例如纤溶酶原激活物抑制剂（PAI）-1，以及由LPS引起的丝裂原激活蛋白（MAP）激酶、细胞外信号调节激酶1/2的活性，但对抗炎基因表达影响不大。抵抗素还增强 LPS 引起的纤维蛋白沉积（止血指标）。通过抑制凝血级联、水蛭素或阻断 MAP 激酶信号 U0126 [1,4-二氨基-2,3-二氰基-1,4-双（2-氨基苯硫基）丁二烯]，LPS + 抵抗素引起的 PAI-1 表达增加、纤维蛋白沉积和肝损伤几乎完全被阻止，表明这些途径在观察到的增强中发挥了因果作用。 抵抗素引起的肝损伤。总而言之，抵抗素引起的 LPS 诱导的肝损伤的增强似乎至少部分涉及通过最有可能涉及凝血级联和纤维蛋白积累的机制上调肝脏炎症。这些数据还表明，抵抗素可能在小鼠肝脏中具有促炎作用，与其对胰岛素信号传导的影响无关，类似于之前在人类中的研究。
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.