中文摘要：

目的：肥胖是2型糖尿病的高危因素,但脂代谢异常引起胰岛素抵抗的分子机制仍需探讨。去乙酰化酶SIRT1在细胞内的糖脂代谢过程中起着重要的作用,本文应用体内外模型探讨不同类型高脂状态下肝细胞内SIRT1蛋白表达的改变,进而揭示肥胖引起2型糖尿病发病的可能分子途径。方法：分别采用含有不同浓度棕榈酸或油酸的培养液培养HepG2肝细胞1天,检测细胞内SIRT1的蛋白水平;同时采用高脂饲料造小鼠肥胖模型,检测肝脏组织内SIRT1的表达改变。结果：三种不同浓度的棕榈酸均未引起HepG2肝细胞内SIRT1表达的改变,与棕榈酸有所不同,两种浓度的油酸均引起细胞内SIRT1表达的显著降低,分别是对照组的65%和58%。在高脂动物模型中同样未发现肝组织内SIRT1蛋白表达的改变。结论：SIRT1作为细胞内糖脂代谢通路的交叉点,其表达的改变有利于揭示脂代谢异常是如何引起糖代谢紊乱的。油酸的大量摄入可以导致甘油三酯在肝脏中的蓄积和影响肝细胞的胰岛素敏感性,而本文提示油酸诱导的细胞代谢改变很可能通过下调SIRT1来实现,其表达的改变为探讨肥胖引起2型糖尿病的分子机制提供线索。

英文摘要：

Objective： Obesity is a high risk factor of type 2 diabetes.However,the molecular mechanism of insulin resistance induced by lypotoxicity still need to be elucidated.Deacetylase SIRT1 plays important roles in the metabolism of glucose and lipid in vivo.The aim of this paper is to investigate the alteration of SIRT1 protein levels in hepatocytes under different types of high fat state,which is helpful for us to realize the possible pathogenesis of type 2 diabetes.Methods： HepG2 cells were treated with different concentrations of palmitic acid or oleic acid for 1 day.And the expression of SIRT1 was detected.Meanwhile,mice were fed with high fat diet for several months and the expression of SIRT1 in liver was determined.Results： Palmitic acid did not alter the expression of SIRT1 in HepG2 cells.Unlike the role of palmitic acid,the expression of SIRT1 was significantly decreased in cells treated with 300 μM oleic acid（65 %） and 500 μM oleic acid（58 %） compared to control.There was no significant change of SIRT1 expression in the liver of high fat mice.Conclusion： SIRT1 regulates many cellular pathways involved in glucose and lipid homeostasis.The alteration of SIRT1 expression helps us to realize the possible molecular pathway of glucose metabolism disorders induced by lypotoxicity.Excessive intake of oleic acid can induce the accumulation of triglycerides and insulin insensitivity in liver.Our data suggested that oleic acid may induce cellular dysfunction through downregulating SIRT1 expression,which provided a clue for us to reveal the mechanism of lypotoxicity in type 2 diabetes.