Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats

BackgroundStudies have demonstrated that resveratrol (a natural polyphenol) and caloric restriction activate Sirtuin-1 (SIRT1) and induce autophagy. Furthermore, autophagy is induced by the SIRT1-FoxO signaling pathway and was recently shown to be a critical protective mechanism against non-alcoholic fatty liver disease (NAFLD) development. We aimed to compare the effects of resveratrol and caloric restriction on hepatic lipid metabolism and elucidate the mechanism by which resveratrol supplementation and caloric restriction alleviate hepatosteatosis by examining the molecular interplay between SIRT1 and autophagy.Methods and resultsEight-week-old male Wistar rats (40) were divided into four groups: the STD group, which was fed a standard chow diet; the HFD group, which was fed a high-fat diet; HFD-RES group, which was fed a high-fat diet plus resveratrol (200 mg/kg.bw); and the HFD-CR group, which was fed a high-fat diet in portions containing 70% of the mean intake of the HFD group rats. The groups were maintained for 18 weeks. Metabolic parameters, Oil Red O and hematoxylin-eosin staining of the liver, and the mRNA and protein expression of SIRT1, autophagy markers and endoplasmic reticulum(ER) stress-associated genes in the liver were assessed after the 18-week treatment. We found that resveratrol (200 mg/kg bw) and caloric restriction (30%) partially prevented hepatic steatosis and hepatocyte ballooning, increased the expression of SIRT1 and autophagy markers while decreasing ER stress markers in the liver and alleviated lipid metabolism disorder. Moreover, caloric restriction provided superior protection against HFD-induced hepatic fatty accumulation compared with resveratrol and the effects were associated with decreased total energy intake and body weight.ConclusionWe conclude that the SIRT1-autophagy pathway and decreased ER stress are universally required for the protective effects of moderate caloric restriction (30%) and resveratrol (a pharmacological SIRT1 activator) supplementation against HFD-induced hepatic steatosis.研究背景 已有研究证实，白藜芦醇（resveratrol，一种天然多酚类化合物）与热量限制均可激活沉默信息调节因子1（Sirtuin-1, SIRT1）并诱导自噬。进一步研究表明，自噬可通过SIRT1-FoxO信号通路被激活，且近期研究发现其是非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）发生发展过程中的关键保护性机制。本研究旨在对比白藜芦醇与热量限制对肝脏脂质代谢的调控效应，并通过解析SIRT1与自噬间的分子互作关系，阐明白藜芦醇补充与热量限制缓解肝脂肪变性的分子机制。 方法与结果 选取40只8周龄雄性Wistar大鼠，随机分为4组：标准饲料组（STD组），饲喂普通维持饲料；高脂饮食组（HFD组），饲喂高脂饲料；高脂+白藜芦醇组（HFD-RES组），饲喂高脂饲料并辅以200 mg/kg·bw的白藜芦醇；高脂热量限制组（HFD-CR组），饲喂高脂饲料，但每日进食量为HFD组大鼠平均摄入量的70%。所有大鼠持续饲养18周。干预结束后，检测各组大鼠的代谢相关指标，对肝脏组织进行油红O（Oil Red O）染色与苏木精-伊红（hematoxylin-eosin）染色，并检测肝脏组织中SIRT1、自噬标志物以及内质网（endoplasmic reticulum, ER）应激相关基因的mRNA与蛋白表达水平。结果显示，200 mg/kg·bw剂量的白藜芦醇与30%热量限制均可部分改善肝脂肪变性与肝细胞气球样变，上调肝脏中SIRT1与自噬标志物的表达水平，同时降低内质网应激标志物的表达，进而缓解脂质代谢紊乱。此外，相较于白藜芦醇干预组，热量限制对高脂饮食诱导的肝脏脂肪蓄积的保护效果更显著，其作用与总能量摄入降低和体重下降密切相关。 研究结论 本研究证实，适度30%热量限制与药物性SIRT1激活剂白藜芦醇补充，其对抗高脂饮食诱导肝脂肪变性的保护作用，均依赖于SIRT1-自噬通路的激活与内质网应激的缓解。