高果糖喂养大鼠致脂肪肝的机制及非诺贝特的干预作用

摘要

目的 观察高果糖饮食诱导大鼠脂肪肝的机制及非诺贝特的干预作用.方法 雄性Wistar大鼠随机分为对照组、高果糖组和非诺贝特组[高果糖喂养第8周后给予非诺贝特30 mg/(kg·d)],喂养12周后处死大鼠并测定各组大鼠血清丙氨酸氨基转移酶(ALT)、门冬氨酸氨基转移酶(AST)、总胆固醇(TC)、游离甘油三酯(TG)及肝脏TG含量;测定脂肪酸合酶(Fas)、内质网应激相关蛋白免疫球蛋白重链结合蛋白(Bip)的表达,自噬相关蛋白自噬相关基因(Atg7)、酵母自噬相关蛋白6同系物(beclin1)、自噬标记轻链蛋白3(LC3)及自噬相关通路哺乳动物雷帕霉素靶蛋白(mTOR)蛋白表达.结果 与对照组和非诺贝特组相比,高果糖组的血AST、血TC、血游离TG及肝TG均显著增高(均P<0.01).与对照组和非诺贝特组比较,高果糖组大鼠的肝内Fas、Bip、mTOR表达增加,Atg7、beclin1、LC3表达降低.结论 长期高果糖喂养引起大鼠肝脏脂质沉积及肝细胞损伤,并伴有肝脏内质网应激及自噬改变,非诺贝特治疗可改善高果糖饮食诱导的脂肪肝和肝细胞损伤,其机制可能与非诺贝特影响Fas并改善肝脏内质网应激及自噬有关.%Objective To observe the effect of fenofibrate intervention on high-fructose-feeding-induced liver steatosis in rats and explore the possible mechanism. Methods Male Wistar rats were randomly divided into control group ,high fructose group and fenofibrate group[fenofibrate intervention started after 8 weeks of high fructose feeding ,30 mg/(kg · d)]. Rats were sacrificed after 12-week of high fructose feeding. Serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),total cholesterol(TC),free triglyceride(TG)and liver TG content were determined;protein levels of fatty acid synthase(FAS),endoplasmic reticulum stress mark-er Bip and autophagy markers such as Atg7,Beclin1,LC3 and the related pathway mTOR in liver tissues were de-tected. Results Compared with those in control group and fenofibrate group,serum AST,serum total cholesterol, blood free TG and hepatic TG were significantly increased in high-fructose group(P < 0.01). The protein expres-sion of Fas,Bip and mTOR were significantly increased in high-fructose group compared with those in control group and fenofibrate group;the protein expression of Atg7,beclin1 and LC3 were significantly decreased in high-fructose group compared with those in control group and fenofibrate group. Conclusions Long-term high-fructose-feeding induces fatty liver and liver cell injury ,and may affect ERS and autophagy. High-fructose-feeding-in-duced fatty liver may be improved by fenofibrate and its underlying mechanism might be associated with Fas,ERS and autophagy in liver.