低氧训练通过SREBP-1-FADS1/2改善非酒精性脂肪性肝炎的作用机制

非酒精性脂肪性肝炎（NASH）是由肝脏脂肪堆积造成的肝脏炎症和损伤，尚无有效治疗药物，但可通过减重和规律运动减缓其发病进程。低氧训练能有效改善脂代谢，但其对NASH的作用机制尚不清楚。我们发现：低氧训练下调单纯性脂肪肝（NAFL）小鼠肝脏调控脂合成的重要蛋白固醇调节元件结合蛋白（SREBP-1）和脂肪酸去饱和酶1/2（Fads1/2）表达，同时改善肝脏多不饱和脂肪酸（PUFA）代谢，减少肝脏炎症。我们提出研究假设：低氧训练通过SREBP-1-Fads1/2通路，调控肝脏PUFA代谢，进而改善NASH表型。本研究目标：从分子、组织器官和动物水平比较低氧训练对NAFL、NASH、肝纤维化（FL）小鼠表型影响；通过动物模型肝脏过表达或敲低Fads1/2，明确Fads1/2在低氧训练改善NASH作用机制及其上游调控机制；为低氧训练防治NASH提供理论基础和新思路。

Nonalcoholic steatohepatitis (NASH) is liver inflammation and damage caused by fat accumulation in the liver, with no effective treatment, it can slow the pathogenesis by weight loss and regular exercise. Exercise in a hypoxic environment was been shown to effectively improve lipid metabolism, but its mechanistic role in NASH is unclear. We previously found that hypoxic training down-regulated sterol regulatory element binding protein (SREBP-1) and fatty acid desaturase 1/2 (Fads1/2) in nonalcoholic simple fatty liver (NAFL) mice and this was accompanied with improvements in liver polyunsaturated fatty acids (PUFA) metabolism and reductions in liver inflammation. We hypothesize that hypoxic training regulates the liver PUFA metabolism by SREBP-1-Fads1/2 pathway, thereby improving the NASH phenotype. The objectives of this study are to compare the phenotypic effects of hypoxic training on NAFL, NASH and liver fibrosis (FL) mice at the molecular, tissue, organ and animal levels;application the liver overexpression or knockdown of Fads1/2 of animal model, to clarify the mechanism of Fads1/2 in hypoxic training improving NASH, and its upstream regulatory mechanism and to provide a theoretical basis and new ideas for NASH prevention and control by hypoxic training.