miR-34a/SIRT1/PPARα通路在铁超载加重脂肪肝过程中的作用

In recent years, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing with the changes of lifestyle and dietary patterns. However, the molecular mechanisms of NAFLD remain unclear. MicroRNAs are recently becoming the focus of attention based on the fact that microRNAs participate in numerous biological processes. miR-34a is found to be possibly associated with the metabolic disorders. Our results indicated that iron overload aggravated the hepatocellular toxicity of free fatty acids. Therefore, we hypothesize that miR-34a/SIRT1/PPARα signaling might play critical roles in iron overload-aggravated NAFLD. In present study, NAFLD models will be established by feeding high fat and high iron to rats and hepatocytes, to investigate the roles of miR-34a/SIRT1/PPARα signaling. miR-34a mimic or anti-miR-34a, SIRT1 and PPARα activators or siRNA will be applied to verify their roles. Lipid metabolism, iron metabolism, oxidative stress and mitochondrial function will be also observed. This study will be aimed at providing a novel idea and tool for the diagnosis and therapy of NAFLD.

近年来非酒精性脂肪肝病（NAFLD）患病率呈不断增长趋势，其发病机制尚未完全阐明。最近microRNA成为研究热点，其中miR-34a可能与代谢性疾病密切相关。我们在前期动物和细胞NAFLD模型中证实，过量铁可加重脂肪酸的肝细胞毒性，故提出miR-34a/SIRT1/PPARα信号通路可能在铁超载加重NAFLD过程中发挥重要作用。本研究拟采用高脂和高铁诱导的NAFLD动物与细胞模型，阐明miR-34a/SIRT1/PPARα通路的作用。通过采用miR-34a模拟物或反义寡聚核苷酸片段、SIRT1和PPARα激动剂或siRNA，从正反两方面验证其在铁超载加重NAFLD过程中的作用，并观察对脂类代谢、铁代谢、氧化应激和线粒体功能的影响，将为NAFLD的诊断和治疗提供一种新的思路和手段。

非酒精性脂肪肝（NAFLD）已成为危害人类健康的主要肝病之一，其发病机制尚未完全阐明。研究发现microRNA的表达与许多疾病的发生密切相关，包括NAFLD。我们之前的研究证实，游离脂肪酸和铁在NAFLD病情发展过程中存在联合作用，而miR-34a在铁超载加重NAFLD发病过程中的作用亟待探讨。因此，本研究在前期基础上采用高脂和高铁饮食诱导NAFLD大鼠模型，采用油酸和铁诱导NAFLD肝细胞模型阐明miR-34a/SIRT1/PPARα通路的作用，并观察对脂类代谢、铁代谢、氧化应激和线粒体功能的影响。动物和细胞实验结果显示，高脂和高铁引起典型的NAFLD病理改变，联合时脂质堆积程度重于高脂单独的作用。miR-34a表达增加，SIRT1和参与脂肪酸氧化的相关基因mRNA和蛋白表达降低，引起线粒体功能障碍和氧化应激。阻断miR-34a或过表达SIRT1可改善脂质堆积和氧化应激。此外，在完成预期研究目标的同时还采用高脂和高铁膳食诱导的NAFLD小鼠模型，尾静脉注射miR-34a慢病毒抑制剂，同样得到减轻肝脏脂质堆积的结果。本研究从正反两方面验证了miR-34a/SIRT1/PPARα通路在铁超载加重NAFLD过程中的作用，提示miR-34a 将来可作为治疗NAFLD的潜在靶点，为NAFLD的诊断和治疗奠定了理论基础。