TFE3 sumo化修饰对非酒精性脂肪肝的作用及机制研究

NAFLD is characterized by abundant triglyceride (TG) accumulation in hepatocytes, which induces hepatic steatosis. Enhancing autophagy-mediated TG degradation in the early course of NAFLD may be of guiding significance for the treatment. Our previous study indicates that TFE3 could increase lysosome-autophagy pathway induced lipophagy, and sumoylation of TFE3 participates in the regulation of TG degradation. Sumoylation site mutation of TFE3 decreases autophagy-induced lipophagy，thus aggravates TG accumulation in hepatocytes. Based on the aboved results, we speculated TFE3 sumoylation regulates the expressions and activites of downstream target genes, augments autophagy-induced TG lipophagy and subsequent PGC1α-mediated fatty acid β-oxidation. Therefore this study will mainly elaborate the following two scientific problems: TFE3 sumoylation functions by regulating the expression of genes related to lysosome biogenesis and autophagy occurrence on the transcriptional level. TFE3 sumoylation accelerates the degradation of TG to fatty acid by stimulating lysosome-autophagy pathway induced lipophagy coupled with PGC1α mediated β-oxidation, eventually alleviates NAFLD. This study is aimed to provide new idea for the study and therapy of NAFLD.

非酒精性脂肪肝（NAFLD）疾病特点是早期大量甘油三酯（TG）在肝细胞内沉积引起肝细胞脂肪变性，加强自噬介导的TG分解对治疗NAFLD具有指导意义。我们前期研究表明TFE3基因可增强自噬介导的TG分解，TFE3的sumo化修饰参与调控NAFLD的TG分解，TFE3 sumo位点突变后自噬介导的TG分解减少,加重NAFLD。因此，我们推测TFE3 sumo化修饰转录水平调控其下游靶基因的表达，增加自噬介导的TG分解及PGC1α依赖的脂肪酸β-氧化，缓解NAFLD进展。本研究将主要阐述以下两个科学问题：1. TFE3 sumo化修饰在转录水平调控溶酶体生成及自噬相关基因表达；2. TFE3 sumo化修饰通过影响自噬主导的脂解作用，促进TG分解为游离脂肪酸，同时调控TFE3下游靶分子PGC1α所介导的脂肪酸β-氧化，最终缓解NAFLD。本研究旨在为NAFLD发病机制及治疗的研究提供新的思路。

非酒精性脂肪肝（NAFLD）疾病特点是早期大量甘油三酯（TG）在肝细胞内沉积引起肝细胞脂肪变性，加强自噬介导的TG分解对治疗MAFLD具有指导意义。本研究表明TFE3的sumo化修饰参与调控NAFLD的TG分解，在转录水平调控溶酶体生成及自噬相关基因表达，增强自噬介导的TG分解，而TFE3 sumo位点突变后自噬介导的TG分解减少,加重NAFLD。我们进一步发现TFE3 sumo化修饰转录水平调控其下游靶基因的表达，增加自噬介导的TG分解及PGC1α依赖的脂肪酸β-氧化，缓解NAFLD进展。本研究旨在为NAFLD发病机制及治疗的研究提供新的思路。