摘要
高脂血症（Hyperlipidemia，HLP）是因脂肪代谢或运转异常使血浆的一种或多种脂质高于正常的疾病。因其本身及慢性并发症的危害，再加上高额的治疗费用，使其成为全球性关注的热点问题。HLP与基因缺陷、饮食不当、内分泌失调等因素有关，其病因及发病机制目前尚未完全清楚，其中脂质代谢异常被认为是引发HLP的重要发病机制之一，针对脂质代谢异常的调节成为预防与治疗HLP及其慢性并发症的重要环节。
降血脂西药起效快且疗效肯定，其毒副作用大且价格昂贵；降血脂中药具有多途径、多环节、多靶点，因其毒副作用也无法长期服用；功能性食品兼有中药优点，且长期服用无毒副作用，在预防和治疗代谢性疾病具有独特优势。已有的研究在功能性食品改善HLP患者脂质代谢方面取得一定成果，但对其作用机制缺乏系统、深入的揭示。
本研究以本课题组选育的高花色苷黑米良种“福紫681”的糙米皮（黑米皮）和红米良种“福红819”的糙米皮（红米皮），以及从多种食用菌中筛选出具有调血脂功效的红菇、灵芝、竹荪等为材料，通过比较这五种农产品对高脂饮食大鼠血脂水平的影响，从中筛选出黑米皮为降血脂疗效最为显著的农产品。接着以黑米皮为材料，观察其对高脂血症模型大鼠脂代谢、氧化应激、脏器组织病变等方面的影响，并进一步从脂质吸收、合成、转化及调控等方面探讨降血脂作用的分子机制，以期为治疗高脂血症脂质代谢紊乱提供科学依据。主要研究结果如下：
（一）5种农产品对高脂饮食大鼠血脂水平的影响
通过长期高脂饮食喂养建立HLP大鼠模型，该实验模型动物表现为毛色偏黄、体重增加较快、不好动、血清TC（总胆固醇）和TG（甘油三酯）升高，符合高脂血症的临床特点。应用黑米皮、红米皮、红菇、灵芝、竹荪对HLP大鼠实验8周,以辛伐他汀作为阳性对照药，观察高脂血症大鼠体重、血清TC、TG水平的变化。结果表明：（1）高脂血症大鼠灌胃辛伐他汀、黑米皮、红米皮、红菇、灵芝和竹荪1-7周，大鼠体重增长均呈现逐渐增加趋势，但与模型组相比，其体重增长速度趋缓；在7-8周，只有黑米皮组的大鼠体重下降，而其他各组体重仍然继续增加；8周后，辛伐他汀、黑米皮、红米皮、红菇、灵芝和竹荪组体重增幅分别降低26.26%、33.16%、39.40%、34.97%、32.15%和6.19%。由此说明，上述5种农产品均可以降低食用高脂饲料大鼠的体重，其中黑米皮对控制大鼠体重效果最为显著。（2）辛伐他汀、黑米皮、红菇、灵芝、竹荪均能不同程度降低HLP大鼠血清的TC、TG含量，其中TC分别下降了18.97%、17.82%、35.06%、27.41%、36.78%，TG分别下降52.00%、57.33%、8%、10.06%、54.67%，而红米皮则升高血清的TC和TG含量，其值分别为12.07%、18.67%。以上试验数据表明，黑米皮对大鼠血脂水平的综合调制效果最为显著，因此选择黑米皮进行进一步试验。（二）黑米皮对高脂饮食大鼠脂代谢的影响
分别以0.09g/mL和0.045g/mL剂量的黑米皮混悬液20mL/kg对HLP模型大鼠实
验8周，以辛伐他汀作为阳性对照药，观察黑米皮对HLP模型大鼠体重变化、血脂水平、载脂蛋白、氧化应激、FFA（游离脂肪酸）水平及粪便脂质的影响。结果表明：(1)黑米皮给药8周后，大鼠体重增加得到明显的抑制，并且与剂量呈正相关；与模型组相比较，黑米皮高、低剂量组体重增幅分别降低了33.16%和24.00%。（2）高、低剂量的黑米皮均能显著降低大鼠的降低血清TC、TG、AI（动脉硬化指数）、ApoB（载脂蛋白B）水平，上升HDL-C（高密度脂蛋白胆固醇）、ApoAI（载脂蛋白AI）含量，并且与剂量呈正相关。其中TC分别下降了17.82%和19.54%，TG分别下降了57.33%和17.33%，AI值分别降低了39.81%和23.65%，ApoB分别降低30.83%和30.83%，同时HDL-C分别提高了24.24%和3.03%，ApoAI分别升高了73.68%和68.42%。（3）高、低剂量的黑米皮能够明显降低血清MDA（丙二醛）含量，升高SOD（超氧化物歧化酶）、CAT（过氧化氢酶）、GSH-Px（谷光甘肽过氧化物酶）活性；其中MDA含量比模型组分别降低了33.24%和28.92%，与正常组接近；SOD活性比模型组分别上升了28.60%和32.46%，与正常组无明显差异；CAT活性比模型组分别上升了101.16%和97.69%，接近正常组；GSH-Px活性比模型组分别上升了32.46%和28.60%，显著高于正常组。（4）高、低剂量的黑米皮能够明显降低血清FFA、粪便TC，升高粪便TG含量。其中FFA含量略高于正常组，分别比模型组分别降低了31.54%和39.08%，粪便TC分别比模型组降低36.75%和53.23%，TC含量分别比模型组升高20.37%和5.56%。（三）黑米皮对高脂饮食大鼠脏器组织的保护作用
分别以0.09g/mL和0.045g/mL剂量的黑米皮混悬液20mL/kg对HLP大鼠实验8周，以辛伐他汀作为阳性对照药，观察黑米皮对HLP模型大鼠肝脏形态和重量、脂肪重量、血清肝酶及肝脏、主动脉和心脏脂肪病变的影响。结果表明：（1）黑米皮能够明显降低肝脏和脂肪指数。大鼠试验8周后，与模型组相比较，黑米皮高、低剂量组肝指数分别降低了12.26%和10.63%，脂肪指数分别降低了35.71%和24.29%。（2）显著降低肝脏的TC、TG水平和血清肝酶ALT（丙氨酸氨基转移酶）、AST（天门冬氨酸氨基转移酶）活性。其中黑米皮高、低剂量组大鼠肝脏的TC水平分别降低了59.74%和50.80%；TG水平分别降低了40.63%和20.31%；ALT分别降低了64.50%和35.41%；AST分别降低了41.79%和23.10%。（3）黑米皮能明显改善肝脏和主动脉脂肪性病变，与剂量呈正相关。其中黑米皮高剂量组大鼠的肝和主动脉形态接近正常组，低剂量组的肝脏有轻度脂肪肝、主动脉无脂肪肝，而模型组大鼠肝和主动脉均形成了脂肪肝病症。
（四）黑米皮改善高脂饮食大鼠脂质代谢作用的分子机制研究
（1）应用RT-PCR法检测FAS（脂肪酸合成酶）、LCAT（卵磷脂胆固醇脂酰转移酶）、HMG-CoAreductase（羟甲基戊二酰辅酶A还原酶）、CYP7A1（胆固醇7α-羟化酶）及PPARα（过氧化物增殖激活物受体-α）mRNA转录水平，结果表明：黑米皮试验8周后，大鼠肝脏组织的PPARα、CYP7A1mRNA转录水平显著上调，HMG-CoAreductasemRNA转录水平显著下调，LACTmRNA转录水平呈上调的趋势，FASmRNA转录水平呈下调的趋势。（2）应用免疫组化法观察肝脏FAS、LCAT蛋白表达，结果表明：黑米皮试验8周后，大鼠肝脏LACT蛋白翻译水平呈上调趋势，而FAS蛋白翻译水平呈下调趋势。（3）用Westernblot法检测肝脏HMG-CoAreductase、CYP7A1及PPARα蛋白表达，结果表明：黑米皮试验8周后，大鼠肝脏的PPARα、CYP7A1蛋白翻译水平显著上调，HMG-CoAreductase蛋白翻译水平显著下调。提示黑米皮可能通过抑制HMG-CoAreductase的表达，激活PPARα表达，刺激CYP7A1基因启动子，使CYP7A1表达上调，改善脂质代谢异常，进而达到降血脂作用。
The Hyperlipidemia(HLP)is a kind of lipid metabolic disorder. The treatment of the HLP has become a hot global issue because of its harmfuless and chronic complications plus high treatment cost. The HLP is related to gene defect, dietetic irrationality and endocrine dyscrasia, but its cause and pathogenesy remain largely unknown. The abnormal lipid metabolism is considered to be one of the important pathogenesy. The regulation of lipid metabolic abnormalities has become an important link in prevention and treatment of HLP and its chronic complications.
Hypolipidemic drugs work faster and effective, but they are expensive and have toxicity side effects. Chinese herbal medicines have advantages of multiple channels, links and targets, but it cannot be used for long-term period. Functional foods possess the advantages of Chinese herbal medicine and can be long-term used without toxicity side effects, which has demonstrated the unique advantages in the prevention and treatment of some metabolic disease. Many scholars have made some achievements in improving lipid metabolism of HLP. However, the mechanism remains poorly understood and needs further investigation.
In this study, we used two rice varieties, the black brown rice variety "Fuzi681" with high anthocyanin and black pericarp, red rice variety "Fuhong819" with red pericarp, and three mushroom varieties, Russula, mythic fungus, and veiled lady to compare the effect of these five agricultural products on blood lipid levels in high-fat diet rats. From these five agricultural products, we had screened one for lowering blood lipid level significantly. Then we observed its effects on lipid metabolism, oxidative stress, organ and vessels lesions in hypolipidemic rats.
We also investigated the molecular mechanism of hyperlipidemia from the aspects of lipid absorption, synthesis, transformation and regulation. Our research will provide a scientific basis for treatment of metabolic disorders in HLP. The main results are as follows:1Effects of5kinds of agricultural products on the blood lipids level of rats fed with high fat diet
The model of rat HLP is established by long-term high-fat diet. The animals with yellow fur, weight gained fast, lacking physical activity and increased serum TC and TG are fit for clinical characteristics of HLP. Using simvastatin as positive control, we fed HLP rats with black brown rice pericarp (BBRP), red brown rice pericarp (RBRP), Russula, mythic fungus and veiled lady for8weeks to observe the changes of body weight, the level of serum TC, TG in hyperlipidemic rats.The results show that:(l)From the first to seventh week, the weight gain of HLP rats fed with simvastatin, BBRP, RBRP, Russula, mythic fungus, and veiled lady increased gradually, but the growth rate has slowed down compared with the model group. From seventh to eighth week, only the body weight of rats fed with BBRP decreased, but the body weight of rats fed with others continued to increase. After eight weeks, the body weight gain of rats fed with simvastatin, BBRP, RBRP, Russula, mythic fungus, and veiled lady decreased by26.26%,33.16%,39.40%,34.97%,32.15%and6.19%respectively. This indicates that the mentioned above five agricultural products can reduce the weight of rats fed with high fat diet, and the effect of BBRP on weight control is significant.(2) The level of serum TC and TG in HLP rat was reduced by simvastatin, BBRP, Russula, mythic fungus and veiled lady, with the TC ratio18.97%,17.82%,35.06%,27.41%,36.78%respectively and the TG ratio52%,57.33%,8%,10.06%,54.67%respectively. However, serum TC and TG in HLP rat was increased by RBRP with the ratio12.07%and18.67%respectively. Therefore, we chose BBRP to the following experiments.
2Effects of BBRP on lipid metabolism in rats fed with high lipid diet
Using the simvastatin as positive control, we fed the HLP model rats with0.09or0.045g/mL dose of BBRP suspension20mL/kg for8weeks to observe the effect on change of weight, blood lipid, apolipoprotein, oxidative stress, the level of FFA and fecal lipid. The results show that:(1) The body weight gain of rats was significantly inhibited and positively correlated with dosage. The body weight gain was reduced by33.16%and24%in high and low dose group, compared to the model group.(2) The level of serum TC, TG, AI, ApoB was significantly decreased, and the level of HDL-C and ApoAI was increased by high or low dosage of black rice pericarp, which was positively correlated with dosage. The level of TC was decreased by17.82%and19.54%. The level of TG was decreased by57.33%and17.33%. The AI value was decreased by39.81%and23.65%. The level of ApoB was decreased by30.83%and30.83%. The level of HDL-C was increased by24.24%and3.03%. The level of ApoAI was increased by68.42%and73.68%.(3) The level of serum MDA was significantly decreased and the activity of SOD, CAT, GSH-Px was increased by high or low dosage of black rice pericarp. Compared to those in the model group, the level of serum MDA was decreased by33.24%and28.92%. The activity of SOD was increased by28.60%and32.46%, with no significant differences to normal group. Tthe activity of CAT was increased by101.16%and97.69%, closely to normal group. The activity of GSH-Px was increased by32.46%and28.60%, significantly higher than that of normal group.(4) The level of serum FFA and TC in feces was significantly decreased by high or low dose of BBRP, but the level of TG in fecal was increased. The level of FFA was slightly higher than that of normal group, and was decreased by31.54%and39.08%respectively compared to the model group. The level of TC in feces was decreased by36.75%and53.23%respectively, the level of TG in fecal was increased by20.37%and5.56%, compared to the model group.
3Protective effects of BBRP on the organs and tissues of rats fed with high fat diet
Using the simvastatin as positive control, we fed the HLP model rats with0.09or0.045g/mL dose of BBRP suspension20mL/kg for8weeks to observe the effects of BBRP on liver morphology and weight, fat weight, liver enzymes, the fatty lesions of liver, aorta and heart. The results show that:(1) The liver and fat index was significantly decreased by BBRP. After the rats were fed with BBRP for8weeks, the liver index were decreased by12.26%or10.63%, and the fat index were decreased by35.71%and24.29%, respectively, in high or low dosage group compared to model group.(2) The levels of liver TC or TG was significantly decreased and the activity of serum ALT or AST was significantly reduced by BBRP. In the liver of rats fed with high or low dosage BBRP, the level of TC was decreased by59.74%and50.80%; TG decreased by40.63%and20.31%; the activity of ALT decreased by64.50%and35.41%; the activity of AST decreased by41.79%and23.10%.(3) The fatty lesions of liver and aorta can be greatly improved by BBRP, which is positively correlated to dosage. The morphology of liver and aortic in high dose group is close to that of normal group. There are mild fatty lesions in the liver with and no fatty lesions in the aorta in low dose group. However, the fatty lesions were formed both in the liver and aorta of rats in model group.
4Study on the molecular mechanism of improving lipid metabolism of BBRP in rats fed with high fat diet
In order to test the effects of BBRP on the mRNA level of FAS, LCAT, HMG-CoA reductase, CYP7A1and PPARa in rat liver tissue, we performed reverse transcription-PCR (RT-PCR) analysis to show that the mRNA level of PPARa and CYP7A1were significantly up-regulated and the mRNA level of HMG-CoA reductase was significantly down-regulated, the mRNA level of LACT showed an increased tendency and the mRNA level of FAS showed a decreased tendency after BBRP treatment for8weeks.(2) Our results showed that the protein level of LACT showed an increased tendency and the protein level of FAS showed a decreased tendency after BBRP treatment for8weeks through immunohistochemistry.(3) With the method of Western blot, we detected the expression level of HMG-CoA reductase, CYP7A1and PPAR a protein in rat liver. Our results showed that the protein level of PPARa and CYP7A1were significantly up-regulated and the protein level of HMG-CoA reductase was significantly, down-regulated in rat liver after BBRP treatment. This indicated that the expression of HMG-CoA reductase might be inhibited and the expression of PPARa might be induced by BBRP, which stimulated the CYP7A1promoter causing the up-regulation of CYP7A1. As a result, the lipid metabolism was improved and the blood lipid was reduced.
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