Elinav Eran, Ali Mohammad, Bruck Rafi, Brazowski Eli, Phillips Adam, Shapira Yami, Katz Meirav, Solomon Gila, Halpern Zamir, Gertler Arieh
Institute for Gastroenterology and Liver Disease, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Hepatology. 2009 Jan;49(1):278-86. doi: 10.1002/hep.22584.
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 alpha1 procollagen promoter.
Inhibition of leptin-enhanced hepatic fibrosis may hold promise as a future antifibrotic therapeutic modality.
瘦素信号传导参与T细胞极化，并且是肝星状细胞（HSC）促纤维化功能所必需的。尽管存在严重的长期脂肪性肝炎，但瘦素缺乏的ob/ob小鼠不会发生肝纤维化。在此，我们使用我们最近生成的小鼠瘦素拮抗剂（MLA）阻断瘦素信号传导，并使用慢性硫代乙酰胺（TAA）纤维化模型在体内以及使用新鲜分离的原代HSC在体外研究其对慢性肝纤维化的影响。在慢性TAA纤维化模型中，给予瘦素与肝病显著加重以及5周龄至8周龄死亡率达100%相关，而给予MLA或联合给予MLA则显著提高生存率、减轻肝纤维化并降低干扰素γ（IFN-γ）水平。体重、血清胆固醇或甘油三酯未观察到显著变化。在体外，单独或与瘦素一起向大鼠原代HSC给予大鼠瘦素拮抗剂（RLA）可降低瘦素刺激的效应，如α-平滑肌肌动蛋白（α-SMA）表达增加以及α1前胶原启动子的激活。
抑制瘦素增强的肝纤维化可能作为未来抗纤维化治疗方式具有前景。
