Effects Of Different Diets On NAFLD And The Expression Of SIRT1 And Its Target Factors In Rat Liver

Background: The pathological picture of Nonalcoholic fatty liver disease (NAFLD) resembles that of alcohol-induced liver injury, but it occurs in patients who do not abuse alcohol. It encompasses a disease spectrum ranging from simple hepatic steatosis to steatohepatitis (NASH), fibrosis, and cirrhosis. It was considered as the manifestation of metabolic syndrome in the liver. Nowadays, the mechanisms underlying NAFLD are not well understood. High calorie diet is associated with NAFLD, including excessive carbohydrate intake and excessive fat intake, whereas calorie restriction (CR), defined as a reduction of caloric intake with adequate nutrition, is considered to be an effective treatment for NAFLD. It has been demonstrated that SIRT1mediated the physiological effects of CR and it regulated a large number of nuclear receptors which play important role in various critical metabolic processes, including PPARα, PGC-1αand SREBP-1c. The extent to how CR influences these nuclear receptors has not been adequately explored. Furthermore, high calorie diet including whether or not effected expression of SIRT1 and its downstream nuclear receptors, it is not well clear.Objective: We researched the effects of high calorie diet, including excessive carbohydrate and fat diet, and calorie restriction on NAFLD and examined the expression of SIRT1 and its target factors such as SREBP-1c, PGC-1αand PPARαin rat liver, to clear the role of SIRT1 and its target factors in the pathogenesis of calorie associated NAFLD, and providing foundation for the precaution or treatment it.Methods: Forty-eigh male Sprague-Dawley rats were randomized into four groups (12/group).The rats in the normal control group (NC) were fed ad libitum with normal chow, the rats in HFa group were fed with high fat diet, the rats in HFr group were fed with high fructose diet and the rats in the calorie restriction group (CR) were fed with 60% food of NC rats for 12 weeks. Blood samples were collected from tail veins every two week for some parameters observed such as fasting plasma glucose (FPG), fasting serum insulin (FINS), total cholesterol (TC) and triglyeride (TG). At the end of experiment, blood was collected by heart puncture after anesthetization. Rats were then sacrificed by decapitation. The liver was immediately removed for HE stain, and detected the expression of SIRT1 and its target factors SIRT1, PGC-1a, SREBP-1c and PPARa.Results: The liver histology appeared normal in NC and CR group. High calorie diet treatment induced rat liver pathology similar to clinical NAFLD, however, HFa group rats had a significantly microvesicular steatosis, whereas HFr group rats had a significantly macrovesicular steatosis. The expression of SIRT1 and PGC-1a were increased in group CR, whereas they were decreased in group HFr and HFa. The expression of PPARa in group HFa and HFr were decreased. Inversely, the expression of SREBP-1c in group HFa and HFr were increased.Conclusion: High Fat or fructose diet induced rat liver pathology similar to clinical NAFLD. The mechanism may be that high calorie intake represses the expression of SIRT1, promoting the expression of SREBP-1c which required for fatty acid synthesis, and depressing the expression of PPARαwhich is a key modulator of fatty acidβ-oxidation. Although HFa and HFr diet all lead to hepatocyte steatosis, in HFa rats, hepatocyte steatosis is mainly caused by exogenous fat acid accumulation, whereas in HFr rats it is caused by endogenous fat acid accumulation.