靶向FoxO1通过调节脂质代谢影响非酒精性脂肪性肝病的初步机制研究

Effect of FoxO1 on lipid metabolism in non-alcoholic fatty liver disease

目的探讨FoxO1在高脂高胆固醇(high-fat high-cholesterol,HFHC)诱导的非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)小鼠模型中肝脏脂质代谢作用和潜在机制。方法选择8周龄雄性C57BL/6J小鼠18只,分为3组:LFD组小鼠喂养低脂对照饲料;HFHC组小鼠喂养高脂高胆固醇(HFHC)饲料16周;HFHC+AS2856组小鼠在喂养HFHC饲料8周后再给予60 mg/kg/d FoxO1抑制剂AS1842856(简称AS2856)治疗8周。Western blot检测各组小鼠肝脏中FoxO1的磷酸化水平,观察小鼠体质量、肝脏组织形态学改变情况及非酒精性脂肪性肝病活动度评分(non-alcoholic fatty liver disease activity score,NAS),检测血清中谷丙氨酸氨基转移酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate aminotransferase,AST)、甘油三酯(triglyceride,TG)和空腹血糖(fasting plasma glucose,FBG),通过qPCR检测脂质代谢相关基因SREBP1c、FAS、ACC1 mRNA水平。结果FoxO1在HFHC小鼠肝脏中活性增加。与HFHC组相比,HFHC+AS2856组小鼠体重、肝重均明显下降,肝脏脂肪变性减轻以及血清TG水平明显下降(P<0.05),且TG合成相关的基因mRNA水平也显著降低了,包括SREBP1c,FAS和ACC1(P<0.05)。结论FoxO1抑制剂AS2856可下调NAFLD小鼠SREBP1c及其下游基因FAS和ACC1的表达,改善TG的累积,从而减缓肝脏脂肪变性。

Objective To investigate the effect of FoxO1 on hepatic lipid accumulation in a nonalcoholic fatty liver disease(NAFLD)mouse model.Methods Eight-week-old male C57BL/6J mice were randomly divided into three groups:control group mice were fed low-fat control chow;HFHC group mice were fed HFHC chow for 16 weeks;HFHC+AS2856 group mice were fed HFHC chow for 8 weeks and then treated with FoxO1 inhibitor AS1842856(AS2856)at a dose of 60 mg/kg/day for 8 weeks.The total and phosphorylated protein levels of FoxO1 in mouse liver were measured by Western blot.Next,mice were observed for the body mass,morphological alterations in liver histology and pathology scores,serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),triglyceride(TG)and fasting plasma glucose(FBG).The expression of lipid metabolism-related genes SREBP1c,FAS and ACC1 were detected by qPCR.Results The phosphorylation of FoxO1was decreased in the liver of HFHC-induced mice.Meanwhile,compared with the HFHC group,FoxO1 inhibitor AS2856 reduced body weight and liver weight,alleviated hepatic steatosis and significantly downregulated serum TG levels in NAFLD mice(P<0.05).Furthermore,HFHC-induced the expression of TG synthesis-related genes,including SREBP1c,FAS and ACC1,were recovered in the liver of AS2856-treated mouse.Conclusion FoxO1 inhibitor AS2856 down-regulated the HFHC-induced expression of SREBP1c and its downstream genes FAS and ACC1,ameliorates triglyceride accumulation and thus reduces hepatic steatosis in NAFLD mice.