LSDP5调控胰岛素抵抗作用机制的研究

非酒精性脂肪性肝病是导致肝脏胰岛素抵抗的主要原因。深入研究该病理过程中重要的差异表达基因及其作用机制将为新药研发提供理论依据。LSDP5是最新发现的PAT家族蛋白成员，定位于细胞内脂肪滴表面，是防治肝脏脂肪变性及胰岛素抵抗的一个极有前途的干预靶点。本研究拟构建高脂膳食诱导脂肪肝和胰岛素抵抗小鼠动物模型，鉴定LSDP5基因表达谱；在体内实验通过腹腔注射靶向基因反义寡核苷酸特异性抑制肝脏LSDP5表达，在体外实验通过"高表达"和"沉默"真核表达载体上调和下调人肝细胞株LSDP5表达，探讨LSDP5基因对肝脏脂肪变性及胰岛素抵抗的调控作用及分子机制；应用酵母双杂交技术寻找可能与LSDP5有特异性相互作用的蛋白分子，并通过免疫荧光染色、免疫沉降及GST融合蛋白沉降技术，验证蛋白质间的相互作用。期望阐明LSDP5的功能，为非酒精性脂肪性肝病和胰岛素抵抗的发病机制及基因干扰工程研究提供新的有效靶标。

Type 2 diabetes has reached epidemic proportions in the word wide. Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance. The predominant differential expression of genes during the pathologic procedure would contribute to develop new drugs. LSDP5 is located on the surface of intracellular lipid droplets, which is one member of PAT family proteins. It is a potent and promising therapeutic target for liver steatosis and insulin resistance. In the present study, we investigate the differential expression of LSDP5 in high-fat diet induced obese mouse model. In vivo, the expression of LSDP5 is reduced via antisense oligonucleotide (ASO) treatment. In vitro, the expression of LSDP5 is increased or decreased by transfecting of high expression plasmid or LSDP5-siRNA plasmid into HepG2 cell line. We investigate the function of LSDP5 on liver steatosis and insulin resistance. Furthermore, we would underline molecular interactions between LSDP5 and pathways involved in lipid metabolism. We expect to clarify the function of LSDP5 and provide new in sight into the pathogenesis of NAFLD and insulin resistance.