Kupffer细胞在果糖引起的非酒精性脂肪肝中的作用

目的探讨肝脏Kupffer细胞在果糖引起非酒精性脂肪性肝病(NAFLD)中的作用及其可能的机制。方法选取48只雌性ICR小鼠随机分为4组:对照组、果糖组、三氯化钆(GdCl3)组和GdCl3+果糖组。对照组与GdCl3组小鼠均饮用自来水,GdCl3组同时给予GdCl3(10 mg/kg,ip)每周2次;果糖组与GdCl3+果糖组小鼠均饮用30%果糖水溶液,GdCl3+果糖组小鼠同时给予GdCl3(10 mg/kg,ip)每周2次。喂养10周后剖杀所有小鼠,取血清检测甘油三酯(TG)含量;取肝脏组织制备石蜡切片用于病理学检查,制备冰冻切片用于油红O染色;其它肝脏组织用于RT-PCR、Westernblot和肝脏TG含量检测。结果果糖组小鼠血清和肝脏TG含量显著升高,肝脏组织HE和油红O染色显示小鼠肝脏脂质沉积明显,而GdCl3干预明显降低果糖组小鼠肝脏TG含量,同时肝脏脂质沉积明显得到改善;果糖组小鼠肝脏核蛋白固醇调节元件结合蛋白-1c(SREBP-1c)明显激活,其靶基因肝脏脂肪酸合成酶(FAS)、乙酰辅酶A羧化酶(ACC)和硬脂酰辅酶A去饱和酶-1(SCD-1)等TG合成相关酶表达水平显著上调,而GdCl3干预明显抑制肝脏核蛋白SREBP-1c的激活及其靶基因上调。结论果糖引起肝脏组织SREBP-1c激活导致肝细胞TG合成增加。肝脏Kupffer细胞激活在果糖诱导的小鼠肝脏SREBP-1c激活和脂质沉积中起重要作用。

Role of Kupffer cells in fructose-evoked non-alcoholic fatty liver disease

Objective To investigate the role of Kupffer cells in fructose-evoked non-alcoholic fatty liver disease(NAFLD).Methods Forty-eight mice were randomly divided into four groups:control group,fruct-ose group,Gaololinium chloride(GdCl3) group and GdCl3+fructose group.In control group,mice had free drinking tap water.In fructose group,mice had free drinking tap water containing 30% fructose.In GdCl3 group,mice were free drinking tap water and administered with GdCl3(10 mg/kg,ip) twice a week.In GdCl3+fructose group,mice were free drinking tap water containing 30% fructose and administered with GdCl3(10 mg/kg,ip)twice a week.All mice were sacrificed after fed for ten weeks.Blood serum was collected for serum triglyceride(TG)measurement.Liver was collected for RT-PCR,Western blot and hepatic TG measurement,or fixed in neutral-buffered formalin for histological examination,or frozen-fixed in OCT mounting media for Oil red O staining.Results The level of serum and hepatic TG was significantly increased in mice fed with fructose solution as compared with those drinking plain tap water.An obvious hepatic lipid accumulation was determined by HE and Oil Red O staining in fructose-fed mice.The level of hepatic TG was significantly attenuated in mice fed with GdCl3+fructose solution as compared with those drinking fructose solution.In addition,GdCl3 pretreatment prevented hepatic lipid accumulation.Chronic fructose drinking induced hepatic sterol regulated element-binding protein-1c(SREBP-1c)activation.Chronic fructose drinking upregulated the expression of enzymes for TG synthesis,such as fatty acid synthase(FAS),acetyl-CoA carboxylase(ACC)and stearoyl-CoA desaturase 1(SCD-1).GdCl3 pretreatment significantly attenuated SREBP-1c activation and the expression of SREBP-1c target genes.Conclusion The increased hepatic TG synthesis in fructose-fed mice is mainly attributed to hepatic SREBP-1c activation.Kupffer cells activation play an important role on fructose-evoked SREBP-1c activation and lipid accumulation.