IL-6介导运动改善非酒精性脂肪肝炎的机制研究

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease, the pathogenesis of NASH is complicated. There is no effective drug, and exercise is the most effective therapy to improve NASH. Our previous clinical study found that moderate intensity exercise significantly reduced the accumulation of triglyceride in the liver and increased the level of IL-6 in serum. Animal experiments found that exercise significantly increased muscle and serum levels of IL-6, and reduced the lipid accumulation and inflammation in the liver induced by high-fat diet. However, these effects of exercise were abundantly diminished in the IL-6 knockout mice. As the lipid accumulation and inflammation are important components of NASH, we supposed that IL-6 mediated the effect of exercise on the improvement of NASH, and designed the following researches: 1. The effect of exercise on the regulation of lipid metabolism and inflammation in the liver via IL-6; 2. The role and mechanism of IL-6R /STAT3 signaling pathway in hepatocytes to improve NASH; 3. The role and mechanism of IL-6R /STAT3 signaling pathway in liver macrophages to improve NASH. This project may provide more effective strategies in the treatment of NASH.

非酒精性脂肪肝炎（NASH）作为日益高发的慢性肝病，发病机制极为复杂。目前尚无疗效确切的药物，而运动是改善NASH的最有效方式。我们前期人群研究发现，中等强度的运动即可显著降低肝内甘油三酯蓄积，同时上调血清中IL-6的水平。动物实验发现，运动显著上调肌肉和血清中的IL-6水平，并对高脂饮食诱导的肝内脂质蓄积和炎症浸润发挥显著改善作用，在IL-6基因敲除后，运动的改善作用显著下降。由于脂质蓄积和炎症反应是NASH的重要组成元素，我们推测IL-6可介导运动对NASH的改善作用，拟开展以下研究：1. 运动通过IL-6对肝内脂质代谢和炎症反应的调控作用；2. 肝实质细胞内IL-6R/STAT3信号通路对运动改善NASH的作用及机制；3. 肝内巨噬细胞中IL-6R/STAT3信号通路对运动改善NASH的作用及机制。通过这些研究的阐释，为临床预防及治疗NASH提供新的思路和策略。

背景：非酒精性脂肪性肝炎（NASH）是代谢功能障碍相关脂肪肝病（MAFLD）的炎症亚型，其患者人群表现为肥胖型和非肥胖/瘦型两种特征。NASH发病机制极为复杂，目前尚无疗效确切的药物，而运动是改善NASH的有效方式之一。运动显著上调肌肉和血清中的IL-6水平，并对高脂饮食诱导的肝内脂质蓄积和炎症浸润发挥显著改善作用。由于脂质蓄积和炎症反应是NASH的重要组成元素，然而运动/IL-6在不同类型（肥胖型和瘦型）的NASH发生发展中的作用并不明确。本研究主要探讨运动对于不同肥胖程度的NASH的调控作用及机制。.重要结果：运动能够明显改善肥胖型NASH的发生发展，主要表现在体重、体脂率、肝脏病理学变化以及机体糖脂代谢；运动对瘦型NASH的发生发展没有明显影响；运动对肥胖型NASH的有效调控作用主要集中在炎症相关信号通路：趋化因子信号通路、Toll样受体信号通路和C型凝集素样受体信号通路；肝脏IL-6R缺失后，中等强度运动对于肥胖型NASH的改善作用部分减弱。综上所述，我们的数据提示IL-6是运动干预肥胖型NASH的关键调节因子。本研究对了解NASH的病理生物学有明确的意义，并支持激活或上调肝脏IL-6信号通路的策略可能成为改善肥胖型NASH的潜在治疗途径。