| Hypercholesterolemia is the main risk factor of atherosclerosis and coronary heart disease, which threaten life and health of human being severely. Therefore, control and decrease of blood cholesterol level is important for preventing the development of coronary heart disease. The cholesterol-lowering functional foods and nutraceuticals are possible alternative therapies for lowering plasma total cholesterol, especially for patients, whose blood cholesterol level is marginally high but not high enough to warrant the prescription of cholesterol-lowering medication.Capsaicinoids refer to a group of pungent compounds and the main active components of chili peppers. They are the focus of numerous studies because of their extensive biological and physiological properties. Recently, some studies reported that capsaicinoids can promote energy metabolism and suppress the accumulation of body fat, prevent hypertension and improve cardiovascular function. In addition, capsaicinoids possess antioxidant activities that can prevent the oxidation of human LDL. These data suggest that capsaicinoids exhibit cholesterol-lowering effects. However, very little information is available on the effect of administration of capsaicinoids on different aspects of cholesterol metabolism in Vivo and Viro. What’s more, the mechanisms by which capsaicinoids affect cholesterol homeostasis have not been completely clarified yet. The present study aims to investigate the influence of capsaicinoids on the change in cholesterol metabolism and its mechanism. Four parts of work were conducted and the corresponding results are as following:1. The effect of capsaicinoids on plasma and hepatic lipids in female rats fed with high cholesterol dietThis study investigated the doses effect and time effect of capsaicinoids on plasma lipid and hepatic lipid in the rats. Female Sprague-Dawley rats were fed with high-cholesterol diet and orally administered0mg kg-1·bw,4mg kg-1·bw,8mg kg-1·bw and12mg kg-1·bw capsaicinoids daily for4weeks,8weeks and12weeks.The results demonstrated that the plasma Non-HDL-C, TG/HDL-C, and hepatic cholesterol were significantly decreased after treating the rats with4mg kg-1·bw capsaicinoids for8weeks, the plasma lipids and hepatic lipids were remarkably decreased after12weeks, compare with control group. However, the plasma Non-HDL-C and hepatic cholesterol were significantly decreased administrated with8mg kg-1·bw or12mg kg-1·bw capsaicinoids only for4weeks, and effective cholesterol-lowering actions were exhibited after8weeks. What’more, the total bile acid levels in small intestinal contents were significantly increased by treated with each dose of capsaicinoids after4weeks. While only12mg kg-1·bw capsaicinoids could elevate the amount of total bile acid and sterol in feces. In conclusion, the hypocholesterolemic effect of capsaicinoids exhibited dose effect and time effect.2. The influence of capsaicinoids on the change in cholesterol metabolism associated with estrogen deficiency in ovariectomized ratsPeople ingest capsaicin mainly through eating chili in daily life. This study investigated the effect and mechanism of action of capsaicinoids and red pepper on cholesterol metabolism in ovariectomized (OVX) rats. Female Sprague-Dawley rats were subjected to sham operation or ovariectomy. After recovery,24OVX rats were randomly divided into three dietary groups consisting of8rats each using a randomized block design. The sham group (sham-CON) and OVX control group (OVX-CON) were fed with high-cholesterol diets, whereas the capsaicinoids group (OVX-CAP) fed with high-cholesterol plus0.01%capsaicinoids diets, and the red pepper group (OVX-RP) fed with high-cholesterol plus2%red pepper powder diets for3weeks.The results demonstrated that the plasma triacylglycerol and cholesterol concentrations, particularly the LDL-C level, were significantly increased, and triacylglycerol and cholesterol accumulations in the liver were elevated in the OVX rats. However, supplementation of capsaicinoids in diet can favorably modify the plasma lipoprotein profile by decreasing plasma TC, LDL-C, and TG, and reducing the concentrations of hepatic cholesterol and triacylglycerol in OVX rats. The hepatic fat-droplet accumulation was ameliorated by the capsaicinoids-supplemented diet in the OVX-CAP group. These data suggest that capsaicinoids can prevent ovarian hormone deficiency induced hypercholesterolemia. Western blot and real-time PCR analyses revealed that capsaicinoids and red pepper significantly enhanced the expressions of hepatic CYP7A1and TRPV1but did not affect the expression of HMG-CoA reductase, IBABP and ASBT in the OVX rats. In conclusion, Capsaicinoids have cholesterol-lowering effects in OVX rats. The hypocholesterolemic activity of capsaicinoids is caused by the stimulating conversion of cholesterol to bile acids by up-regulation of CYP7A1expression and the increase in fecal total bile acid excretion. Red pepper had a greater efficacy in producing beneficial anti-hyperlipidemic effects in the cholesterol-fed OVX rats.3. The synergistic effect of capsaicinoids and dietary fiber in regulation of cholesterol homeostasisThis study investigated the synergistic effect of capsaicinoids and dietary fiber on cholesterol metabolism in ovariectomized rats. Female Sprague-Dawley rats were performed to ovariectomy. After recovery,32OVX rats were randomly divided into four dietary groups consisting of8rats each using a randomized block design. The OVX control group (CON) was fed with high-cholesterol diets, the dietary fiber group (DF) was fed with high-cholesterol plus5%fiber diets, the high capsaicinoids group (HCAP) was fed with high-cholesterol plus0.01%capsaicinoids diets, and the capsaicinoids+dietary fiber group (DF+LCAP) was fed with high-cholesterol plus5%fiber and0.005%capsaicinoids diets for4weeks.The results demonstrated that body weight gain, plasma lipids and hepatic lipids levels were significantly decreased, while the amount of total bile acid and sterol in feces were dramatically increased in DF+LCAP group rats. What’ more, the concentration of free ammonia and pH of cecal content were significantly increased in HCAP group rats. The0.01%dose of capsaicinoids could promote the growth of Escherichia coli and Enterococcus, and inhibit Bifidobacterium and Lacticacidbacteria in cecal content. However, the administration of5%dietary fiber+0.05%capsaicinoids remarkable increased the concentration of SCFA and the amount of Bifidobacterium and Lacticacidbacteria, and decreased the pH and free ammonia of cecal content in the OVX rats. In conclusion, the combination of dietary fiber and capsaicinoids work synergistically in regulating the homeostasis of cholesterol in OVX rats. In addition, dietary fiber also modifies the injury caused by0.01%capsaicinoids.4. Regulating mechanism of TRPV1on cholesterol metabolism in human hepatocyteLiver is the main organ for endogenous cholesterol synthesis. This study investigated the interaction of administrated0,10nmol/L,100nmol/L,1μmol/L and10μmol/L capsaicin with the mRNA and protein expressions of key receptors and enzymes involved in cholesterol metabolism in human hepatocyte L02. We also used the TRPV1 antagonist capsazepine to explore the involvement and hypocholesterolemic mechanism of TRPV1.The results demonstrated that after treating the human hepatocyte L02with capsaicin48h, the concentration of cholesterol in cell and medium were decreased, while the total bile acid in medium was significantly increased compared with the control group as the dose of capsaicin increased. The1μmol/L and10μmol/L capsaicin have the best effect on the cholesterol-lowering action. In addition, Western blot and real-time PCR analyses revealed that10nmol/L and100nmol/L capsaicin had no effect on the protein and mRNA expression of HMG-CoA reductase, while the1μmol/L and10μmol/L cpacaicin could significantly enhance its expression. The protein and mRNA expression of CYP7A1and TRPV1were dramatically elevated as the capsaicin dose increased.The blockage of TRPV1was obtained by antagonist of TRPV1named capsazepin. In the human hepatocyte L02, the protein and mRNA levels of CYP7A1were up-regulated while the levels of HMG-CoA reducatase were down-regulated by1μmol/L capsaicin, but not in the presence of capsazepine. In conclusion, the cholesterol-lowering effect low dose of of capsaicin in human hepatocyte L02ascribed to stimulating conversion of cholesterol to bile acid. The1μmol/L and10μmol/L capsaicin inhibited the endogenous cholesterol synthesis and promoted cholesterol metabolism. Activation of TRPV1by capsaicin could modulate the expressions of genes involved in cholesterol metabolisms. |
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