FTO抑制自噬导致非酒精性脂肪肝脂质沉积的关键分子机制

Understanding of the epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD) has increased; it is one of the most common causes of chronic liver injury in many countries around the world. NAFLD is commonly associated with obesity, hyperlipidemia, and type 2 diabetes mellitus (DM). Furthermore, it is an independent risk factor for increased cardiovascular disease mortality and obesity related deaths. Several researches have appeared in recent years that the inblance of autophagy have a predominant role in the control of liver lipid accumulation that lead to NAFLD. Fat mass and obesity associated gnen (FTO) is the first gene which was discovered in genome-wide association studies (GWAS) for obesity. Growing evidence suggests that it is participate in the control of energy balance. We found serum FTO levels in patients with NAFLD were significantly higher than those in controlsubjects. FTO could reduce the autophagy level and downregulate the expression of ATG7 and LC3-II/LC3-I, and participate in the formation of fatty liver in rats previously, indicating it plays an important role in the process of liver autophagy and lipid metabolism disorders. In order to study the function of FTO in autophagy and lipid metabolism process, the correlations of FTO and relative indexes would be analyzed on the basis of collecting clinical cases studies. We will elucidate the molecular mechanism of FTO in hepatocyte autophagy and steatosis progress. The findings of this study would indicate the molecular mechanism of FTO in hepatocyte autophagy and fatty degeneration. Moreover, this research will do benefit to improve the diagnostic and treatment of NAFLD.

近年来，非酒精性脂肪性肝病（NAFLD）的发生率逐渐升高，且与肥胖、糖尿病、高脂血症等代谢疾病密切相关。研究发现，自噬作用失衡引起的肝细胞脂质积聚是NAFLD发生发展的关键环节。肥胖相关基因（FTO）已被证实是调节能量代谢的关键基因。我们前期发现NAFLD患者血清FTO水平显著高于正常人群；并证实其参与大鼠脂肪肝的形成；FTO过表达可下调自噬基因ATG7表达及LC3-II/LC3-I比值，减弱自噬水平；这些证据提示该基因在肝脏脂代谢和自噬过程中发挥重要作用。为此，本研究拟通过临床研究进一步明确FTO水平与脂代谢相关指标及自噬的相关性；构建FTO稳定表达和沉默的肝细胞系，油酸诱导肝细胞脂肪变，观察该基因对脂质沉积和自噬水平的影响，进而探索其调控自噬及脂代谢相关基因表达的分子机制。该研究可揭示FTO在NAFLD脂质沉积过程中的关键作用，为NAFLD的防治提供新的策略。

背景：非酒精性脂肪性肝病（NAFLD）的发生率逐渐升高，且与肥胖、糖尿病、高脂血症等代谢疾病密切相关。肥胖相关基因（FTO）已被证实是调节能量代谢的关键基因。前期结果显示其表达与肝细胞脂质沉积及自噬有关。主要研究内容：1. 通过临床研究进一步明确FTO水平与脂代谢相关指标及自噬的相关性；2. 构建FTO稳定表达和沉默的肝细胞系，油酸诱导肝细胞脂肪变，观察该基因对脂质沉积和自噬水平的影响，进而探索其调控自噬及脂代谢相关基因表达的分子机制。重要结果：共入组NAFL患者130人、NASH患者125人，对照组100人，结果发现1. 年龄与NAFLD发生率正相关；较对照组相比男性NAFL及NASH发生率分别为73.1%和78.4%。与对照组相比NAFLD患者BMI, 腰围，臀围，腰臀比,空腹血糖，餐后血糖, TC, TG, LDL, ALT及AST显著增加；NAFL及NASH组HDL水平存在显著差异（1.19±0.16 vs. 1.07±0.10 mmol/L）； NAFLD患者血清FTO水平显著高于正常人群，与对照组(18.57±0.59 ng/L)相比FTO水平显著升高，NAFL及NASH组分别为34.57±1.734 ng/L，45.56±1.58 ng/L；2. 与对照组相比NAFL及NASH组FTO mRNA及蛋白表达水平显著增加。3. FTO过表达可下调自噬基因ATG7表达及LC3-II/LC3-I比值，减弱自噬水平。科学意义：该研究揭示FTO在肝脏脂代谢和自噬过程中发挥重要调控作用，自噬作用失衡引起的肝细胞脂质积聚是NAFLD发生发展的关键环节，为NAFLD的防治提供新的策略。