逍遥散对大鼠肝细胞脂肪变性及内质网/SREBP1/脂代谢通路的影响

目的:从内质网应激及其调控的与脂质合成相关的SREBP1通路的角度探讨逍遥散防治大鼠肝细胞脂肪变性的分子机制。方法:健康Wistar大鼠分为正常对照组、模型组、逍遥散组和东宝肝泰组4组,建立四氯化碳联合高脂饮食诱导大鼠脂肪肝动物模型,观察各组肝组织病理变化、血清肝功能、肝组织中胆固醇(TC)、甘油三脂(TG)含量及肝组织GRP78、SREBP1及生脂相关酶分子的表达。结果:逍遥散组的肝指数(P0.01)、血清ALT(P0.01)、AST(P0.05)水平及肝组织中TG(P0.05)含量较模型组明显降低。病理HE染色显示,逍遥散组肝脂肪变性较模型组明显减轻;RT-PCR和Western blot结果表明,逍遥散组GRP78分子、SREBP1 mRNA及部分生脂相关酶mRNA的表达低于模型组。结论:逍遥散对大鼠肝细胞脂肪变性的抑制作用与内质网应激有关,其可能分子机制为:逍遥散降低内质网应激,引起转录因子SREBP1的表达与入核转位的减少,在细胞核内被SREBP1激活的生脂相关酶基因的诱导表达降低,使肝细胞内甘油三脂、胆固醇合成减少,导致肝细胞脂肪变性的减轻。

Effects of Xiaoyao San on Hepatic steatosis and ER Stress/SREBP1/lipid metabolism pathway in rats

Objective:Through ER stress/SREBP signaling pathway to investigate experimental efficiency and potential mechanisms of Xiaoyao San(XYS) in preventing fatty degeneration of liver cells in rat.Methods: Healthy Wister rats were randomly divided into 4 groups: normal group,model group,XYS group and Dong Bao Gan Tai(DBGT) group.Hepatic steatosis rats were established by carbon tetrachloride(CCL4) subcutaneous injection along with high-fat diet.The followings were detected: pathological changes of liver,liver function,the levels of total cholesterol(TC) or triglyceride(TG) and the expression of GRP78 protein and mRNA,SREBP1mRNA and lipogenic enzymes mRNA in liver tissues.Result: The liver index(P<0.01),levels of serum alanine aminotransferase(ALT)(P<0.01)and aspartate aminotransferase(AST)(P<0.05)and the levels of triglyceride(TG)(P<0.05) in Xiaoyao San-treated rats were significantly decreased than those in model group.The histopathological changes of hepatic steatosis were more notably improved in XYS –treated group than in model group.The expression of GRP78 protein and mRNA,SREBP1 mRNA and parts of lipogenic enzymes mRNA in liver tissues were reduced in XYS group than in model group.Conclusion: Xiaoyao San preventing hepatic steatosis induced by CCL4-is associated with endoplasmic reticulum stress(ER Stress).Potential mechanism is that Xiaoyao San prevents the ER Stress and subsequently decreases translocation and binding of SREBP1 to promoter regions of lipogenic genes which is responsible for triglyeride/cholesterol biosynthesis and accumulation.