O-GlcNAc糖基化通过上调脂肪酸转位酶CD36的表达与功能促进非酒精性脂肪性肝病进展的机制研究

NAFLD已跃居为我国慢性肝脏疾病的首位。然而，目前对其发病机制的认识尚不清楚, 严重限制了该疾病的诊治。CD36是驱动NAFLD发生、发展的重要因子，但其功能调节的机制仍亟待研究。申请人前期研究证实O-GlcNAc糖基化作为细胞的“能量感受器”，在NAFLD患者肝脏组织中显著升高；通过高通量筛选发现O-GlcNAc糖基化的升高促进CD36基因转录，且在体外标记实验中首次证实CD36蛋白可被该糖基化修饰，提示O-GlcNAc糖基化密切参与CD36表达与功能的调控。本课题将进一步利用模式动物、蛋白点突变和质谱技术，阐明肝脏细胞代谢紊乱通过升高O-GlcNAc糖基化促进CD36表达与功能，进而导致肝脏脂质储积并加重代谢紊乱的机制，并由此形成恶性反馈，最终促进NASH的进展。本研究有望从蛋白质翻译后修饰的角度揭示代谢紊乱促进NAFLD进展的内在因素，为干预NAFLD奠定新的理论依据和实验基础。

Non-alcoholic fatty liver disease (NAFLD) has become the first chronic liver disease in China. However, the understanding of its pathogenesis is still unclear. It was reported that CD36 was an important factor driving the occurrence and development of NAFLD. However, the mechanism of its increased expression and functional regulation in NAFLD still needs to be studied. O-GlcNAcylation plays an important role as a nutrient sensor and is correlated with glucose and lipid metabolism. Our previous studies had confirmed that O-GlcNAc modification is significantly increased in liver tissues of NAFLD patients. In addition, by PCR-array screening, we found that the increase of glycosylation promoted the transcription of CD36, and in vitro O-GlcNAc labeling experiments confirmed for the first time that CD36 protein could be directly modified by O-GlcNAcylation , suggesting that O-GlcNAc glycosylation is closely involved in the regulation of CD36 expression and function. In this project, we will further use animal model, point mutants of protein and mass spectrometry technology to reveal the molecular mechanisms of O-GlcNAc promotes the progression of NAFLD by upregulation the expression and function of CD36. That high fat absorption and metabolic disorder of liver cells could increase the level of O-GlcNAcylation, and thus upregulate the expression and function of CD36. Furthermore, upregulation of CD36, the key molecule for fatty acid uptake, leads to increased fat uptake and metabolic disorder of liver cell, forming a vicious cycle that promotes the progression of NAFLD. Therefore, by this project, we expecte to reveal the molecular mechanisms of how O-GlcNAc promotes the progression of NAFLD by upregulating the expression and function of CD36, which will provide new insight into the potential theoretical basis for the intervention of NAFLD.