Competitive Inhibition of Leptin Signaling Results in Amelioration of Liver Fibrosis Through Modulation of Stellate Cell Function
Competitive Inhibition of Leptin Signaling Results in Amelioration of Liver Fibrosis Through Modulation of Stellate Cell Function
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DOI：
10.1002/hep.22584
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发表时间：
2009-01-01
期刊：
影响因子：
13.5
通讯作者：
Gertler, Arieh
中科院分区：
文献类型：
--
作者：
Elinav, Eran;Ali, Mohammad;Gertler, Arieh
瘦素信号传导参与T细胞极化，并且是肝星状细胞（HSC）的促纤维化功能所需的。瘦素缺乏的ob/ob小鼠不发展肝纤维化，尽管存在严重的长期脂肪性肝炎。在这里，我们用我们最近产生的小鼠瘦素拮抗剂（MLA）阻断瘦素信号传导，并使用慢性硫代乙酰胺（TAA）纤维化模型在体内和体外使用新鲜分离的原代HSC检查对慢性肝纤维化的影响。在慢性TAA纤维化模型中，瘦素给药与显著增强的肝脏疾病和100%的5周至8周死亡率相关，而MLA给药或联合给药显著改善了生存率，减轻了肝纤维化，降低了干扰素γ（IFN-γ）水平。未观察到体重、血清胆固醇或甘油三酯的显著变化。在体外给予大鼠瘦素拮抗剂（RLA），无论是单独或与瘦素，大鼠原代HSC瘦素刺激的影响，如α-平滑肌肌动蛋白（α-SMA）的表达增加，和激活α 1前胶原启动子减少。结论：抑制瘦素增强的肝纤维化可能是未来的抗纤维化治疗方式。（肝脏学2009;49：278-286。）
Leptin signaling is involved in T-cell polarization and is required for profibrotic function of hepatic stellate cells (HSCs). Leptin-deficient ob/ob mice do not develop liver fibrosis despite the presence of severe long-standing steatohepatitis. Here, we blocked leptin signaling with our recently generated mouse leptin antagonist (MLA), and examined the effects on chronic liver fibrosis in vivo using the chronic thioacetamide (TAA) fibrosis model, and in vitro using freshly-isolated primary HSCs. In the chronic TAA fibrosis model, leptin administration was associated with significantly enhanced liver disease and a 100% 5-week to 8-week mortality rate, while administration or coadministration of MLA markedly improved survival, attenuated liver fibrosis, and reduced interferon gamma (IFN-gamma) levels. No significant changes in weight, serum cholesterol, or triglycerides were noted. In vitro administration of rat leptin antagonist (RLA), either alone or with leptin, to rat primary HSCs reduced leptin-stimulated effects such as increased expression of alpha-smooth muscle actin (alpha-SMA), and activation of alpha 1 procollagen promoter. Conclusion: Inhibition of leptin-enhanced hepatic fibrosis may hold promise as a future antifibrotic therapeutic modality. (HEPATOLOGY 2009;49:278-286.)