Abstract
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.
Highlights
Non-alcoholic fatty liver disease (NAFLD, characterized by steatosis) is one of the most common manifestations of chronic liver disease [1] and its prevalence is a serious and increasing clinical problem worldwide
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 Endoplasmic reticulum (ER) stress markers in the liver and alleviated lipid metabolism disorder
We conclude that the SIRT1-autophagy pathway and decreased ER stress are universally required for the protective effects of moderate caloric restriction (30%) and resveratrol supplementation against high-fat diet (HFD)-induced hepatic steatosis
Summary
Non-alcoholic fatty liver disease (NAFLD, characterized by steatosis) is one of the most common manifestations of chronic liver disease [1] and its prevalence is a serious and increasing clinical problem worldwide. Some studies suggested that caloric restriction reversed metabolic dysfunction in the liver and induced a specific lipidomic and metabolomic reprogramming event in the mouse liver [10, 11] This evidence indicates that caloric restriction may be a potential therapeutic approach to NAFLD, but the molecular mechanism of any such connection remains unknown. Endoplasmic reticulum (ER) stress is evident in the liver of obese animals [24] and is considered to play a key role in the regulation of lipogenesis as well as hepatic steatosis [25] It is still unknown whether resveratrol, by mimicking the effects of caloric restriction prevents hepatic steatosis by regulating the SIRT1-autophagy pathway and alleviates ER stress. 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
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