胆汁酸核受体FXR在非酒精性脂肪性肝病中的作用

背景:肝细胞内三酰甘油堆积和胰岛素抵抗是非酒精性脂肪性肝病(NAFLD)的基本特征,贯穿NAFLD的整个病程。胆汁酸对食物性脂类的吸收和胆同醇代谢具有重要调控作用,亦是平衡糖脂代谢的重要信号分子,其主要通过法尼酯衍生物X受体(FXR)发挥作用。目的:评估FXR激动剂GW 4064对肝细胞内脂质堆积和三酰甘油含量的潜在作用,同时探讨FXR在NAFLD患者肝组织中的表达情况。方法:以软脂酸和油酸(2:1)混合液处理人张氏肝细胞株,建立肝细胞脂肪变性模型,干预组予FXR激活剂GW 4064(10μmol/L)处理。以油红染色测定细胞内脂质含量,并检测三酰甘油含量。以免疫组化法检测正常对照组和NAFLD患者肝组织中的FXR表达情况。结果:FXR激活剂GW 4064可明显减少脂肪变肝细胞中脂滴和三酰甘油含量。FXR在NAFLD患者肝组织中的表达率显著低于正常对照组(P0.01)。结论:FXR激动剂GW 4064可有效缓解肝细胞的脂肪变程度;FXR在NAFLD患者中的表达受抑制。FXR改善NAFLD的分子机制值得进一步研究。

Role of Bile Acid Nuclear Receptor FXR in Nonalcoholic Fatty Liver Disease

Background： Nonalcoholic fatty liver disease （NAFLD） is characterized by excessive accumulation of triglyeerides in hepatocytes and insulin resistance, which progress throughout the disease course. Besides its role in dietary lipid absorption and cholesterol homeostasis, bile acids are important signaling molecules, which play important roles in glucose and lipid metabolism through the farnesoid X receptor （FXR）. Aims： To assess the potential role of FXR agonist GW 4064 in hepatic lipid accumulation and triglyceride content; and to explore the expression of FXR in liver tissue of NAFLD patients and normal controls. Methods： Model of steatosis was constructed in Chang liver cell line by incubation with mixture of palmitic acid and oleie acid at ratio of 2：1; the intervention group was exposed to FXR agonist GW 4064 （10 μmol/L）. Lipid content was determined by oil red staining and triglyeeride content was measured. The FXR expression in liver tissue of NAFLD patients and normal controls was determined immunohistocbemically. Results： Significant reductions of lipid droplets and triglyceride content were observed when the cells were exposed to GW 4064. Expression of FXR in liver tissue of NAFLD patients was significantly reduced compared to normal controls （1~〈0.01）. Conclusions： FXR agonist GW 4064 can ameliorate hepatic steatosis effectively. Expression of FXR is decreased in NAFLD patients, and the molecular mechanism of FXR in ameliorating NAFLD is worth for further study.