摘要
第一部分绿茶多酚对高脂诱导代谢紊乱的影响
目的：观察高脂膳食对大鼠代谢指标的影响和肝脏脂肪沉积以及肝脏糖脂代谢相关基因表达的影响，并观察绿茶多酚对高脂膳食诱导的代谢改变、肝脏脂肪沉积和糖脂代谢基因表达改变的干预效果。
方法：体重40-60g断乳雄性Wistar大鼠50只，适应性喂养一周后，分为5组，对照组给予标准饲料，高脂组和三个绿茶多酚干预组给予高脂饲料，实验开始时所有大鼠饮用去离子水，绿茶多酚干预组在达到成年体重后改为饮用不同浓度的绿茶多酚水溶液，第26周进行口服糖耐量试验(OGTT)，26周末，处死大鼠，分离血清。用ELISA检测血清中胰岛素的含量；用生化试剂盒检测血糖、血脂水平，计算HOMA-IR指数；精确称量肝脏、睾周脂肪和肾周脂肪的重量，计算内脏脂肪系数和肝脏系数；取部分肝脏组织冰冻切片，进行油红O染色。采用实时荧光定量PCR方法检测肝脏组织中脂肪合成酶(FAS)、羟甲基戊二酸单酰辅酶A还原酶(HMG CoAR)、过氧化物酶体增殖物激活受体α (PPARα)、固醇调节元件结合蛋白-1c(SREBP-1c)、葡萄糖6磷酸酶(G6Pase)、磷酸烯醇式丙酮酸羧激酶(PEPCK)和葡萄糖转运蛋白2(GLUT2)的mRNA表达水平。
结果：对照组大鼠进食量显著高于其它组，但是各组大鼠能量摄入量没有显著差异。自第9周开始，高脂组大鼠体重显著高于对照组，这种差异持续到实验结束。实验结束时，高脂组大鼠体重和内脏脂肪系数都显著高于对照组，与高脂组相比，绿茶多酚干预组大鼠的体重和内脏脂肪系数都显著降低。与对照组相比，高脂组大鼠空腹血糖水平、空腹胰岛素水平，胰岛素抵抗指数和OGTT试验曲线下面积都显著升高，绿茶多酚干预降低了高脂饲养大鼠的血糖水平，胰岛素抵抗指数和OGTT试验曲线下面积，但是对胰岛素水平没有明显影响。高脂饲养导致了大鼠血脂紊乱，其中血清甘油三酯(TG)，低密度脂蛋白胆固醇(LDL-C)和总胆固醇(TC)水平与对照组相比显著升高，高密度脂蛋白胆固醇(HDL-C)水平显著下降，LDL-C/HDL-C值显著上升，绿茶多酚干预降低了高脂饲养大鼠血清TG、TC、LDL-C、LDL-C/HDL-C的水平，但是对HDL-C的水平没有明显影响。高脂饲养引起了大鼠肝脏脂肪沉积，肝脏系数升高，并引起了肝脏中糖脂代谢相关基因的表达改变，其中脂肪合成相关的基因FAS、HMG-CoAR和SREBP-1和糖异生关键限速酶PEPCK和G6Pase的mRNA表达水平显著升高，脂肪酸氧化相关的基因PPARα和肝脏中主要的葡萄糖转运体GLUT2的mRNA表达水平显著降低。绿茶多酚干预降低了高脂饲养大鼠的肝脏系数和肝脏脂肪沉积，并抑制了高脂诱导的大鼠肝脏糖脂代谢基因表达改变。
结论：高脂饲养诱导大鼠发生代谢紊乱，肝脏脂肪沉积和糖脂代谢相关基因的表达异常，这些改变与能量摄入无关；绿茶多酚干预能够预防和改善高脂诱导的代谢紊乱和肝脏脂肪沉积。
第二部分绿茶多酚对脂联素水平的影响及细胞信号机制
目的：绿茶多酚的代谢调节机制到目前为止尚不清楚。脂联素被认为是肥胖和胰岛素抵抗治疗的新靶点。本部分主要观察绿茶多酚对高脂饲养大鼠脂联素水平的影响并探索相关机制。
方法：动物饲养与干预同第一部分，血清脂联素水平采用ELISA方法检测，用实时荧光定量PCR检测大鼠内脏脂肪组织中脂联素和PPARγ的mRNA表达水平，采用免疫印迹法检测PPARγ，磷酸化PPARγ，细胞外信号调节激酶ERK1/2和磷酸化ERK1/2的蛋白表达水平。采用高糖DMEM培养基体外培养大鼠内脏脂肪组织，并进行绿茶多酚进行干预和ERK1/2的特异性抑制剂PD98059进行预处理。干预24h后，收集培养液，检测其中的脂联素水平，收集培养的内脏脂肪组织检测脂联素和PPARγ的mRNA表达水平以及PPARγ，磷酸化PPARγ，ERK1/2和磷酸化ERK1/2的蛋白表达水平。
结果：高脂组大鼠脂联素mRNA水平和血清脂联素水平都显著低于对照组，而绿茶多酚干预显著升高了脂联素水平。与对照组相比，高脂组大鼠内脏脂肪中ERK1/2的激活和PPARγ的磷酸化显著升高，而PPARγ的mRNA水平和蛋白表达水平显著降低，与高脂组相比，绿茶多酚干预组ERK1/2和PPARγ磷酸化水平显著降低，而PPARγ表达水平显著升高。采用高糖体外培养内脏脂肪组织也显著降低了内脏脂肪组织中脂联素mRNA水平，分泌到培养液中的脂联素水平和PPARγ的表达水平，而上调了ERK1/2和PPARγ的磷酸化水平。而绿茶多酚干预和ERK1/2抑制剂处理均能抑制高糖培养诱导的这些改变。
结论：上调脂联素水平是绿茶多酚抑制高脂饮食诱导代谢紊乱的重要机制之一。绿茶多酚通过抑制ERK1/2的激活，降低PPARγ的磷酸化水平和上调PPARγ表达水平来上调脂联素的水平。
第三部分绿茶多酚对血管内皮高通透性的影响及机制
目的：观察高脂饲料饲养大鼠主动脉内皮通透性的改变和绿茶多酚的干预效果，并在体内、体外细胞实验中探索绿茶多酚调控通透性改变的机制。
方法：动物饲养与干预同第一部分，牛主动脉内皮细胞(BAECs)采用高糖培养基培养，分别采用绿茶多酚，二苯基碘(DPI)、SU5416(VEGF受体2抑制剂)、rhVEGF和β环糊精（胞膜窖结构抑制剂)进行干预后，检测单层BAECs通透性。大鼠主动脉内皮通透性采用伊文思蓝注射法测定，单层BAECs通透性利用穿过细胞的异硫氰酸荧光素(FITC)-右旋糖酐测定。采用二氢乙啶(DHE)荧光探针检测大鼠主动脉活性氧(ROS)水平，采用2',7'-二氯荧光素二乙酸酯(DCFH-DA)荧光探针检测细胞中的ROS水平。采用实时定量PCR方法检测VEGF和窖蛋白1的mRNA表达水平，采用ELISA检测大鼠血清和细胞培养液中的VEGF水平，采用蛋白免疫印迹法检测培养的BAECs中的cav-1蛋白表达水平。
结果：与对照组相比，高脂组大鼠主动脉通透性显著升高，与高脂组相比，绿茶多酚干预组主动脉通透性显著降低。高脂膳食显著上调了大鼠的血清VEGF水平、主动脉中VEGF的mRNA表达水平和主动脉中的ROS水平，而绿茶多酚干预显著抑制了高脂诱导VEGF和ROS水平的升高。采用高糖培养基体外培养BAECs，显著上调了单层BAECs的通透性、VEGF的表达和分泌水平、以及细胞内ROS水平，同时还上调了NADPH氧化酶亚基p22phox和p67phox亚基的表达水平，并诱导了窖蛋白1表达水平升高，而绿茶多酚显著改善了高糖诱导的BAECs通透性、VEGF的表达和分泌水平、ROS、NADPH氧化酶亚基和窖蛋白1表达水平的升高。与高糖培养类似，rhVEGF预处理显著升高了普通培养基培养的单层BAECs的的通透性，而VEGF受体抑制剂SU5416预处理、NADPH氧化酶抑制剂DPI预处理和检测前采用胞膜窖结构抑制剂β环糊精孵育都显著降低了高糖培养单层BAECs的通透性，SU5416预处理还显著降低了窖蛋白1的表达水平。
结论：高脂膳食能够诱导大鼠主动脉内皮通透性升高，这种效应能够被绿茶多酚有效改善。绿茶多酚调节高脂饲养大鼠内皮通透性的可能信号途径为：下调NADPH氧化酶表达水平，降低ROS产生，进而下调VEGF水平，降低窖蛋白1的表达水平，减少胞膜窖介导的大分子转运，改善内皮高通透性。
Part1The effect of GTPs on high-fat diet induced metabolic disorders
Objective: The metabolic abnormalities associated with metabolic syndrome includeobesity, hyperglycemia, dyslipidemia, elevated blood pressure and decreased insulinsensitivity. Liver is the biggest and most important organ that regulates metabolism,and fatty liver is considered to be a performance of the metabolic syndrome in liver.This part of the study investigated the effect of high-fat diet on metabolic markers inrats, liver fat deposition and expression of genes related to glucose and lipidmetabolism in the liver, the effects of GTPs on high-fat diet-induced metabolicchanges was focused.
Methods: Male SPF Wistar rats after weaning and weight between40-60g were used.After acclimation for a week, the rats were randomly divided into the following fivegroups: the control group, fed on standard chow and drank deionized water; the highfat group, fed on high fat diet, drank deionized water; three GTPs treated groups,fed on high fat diet, and the deionized drinking water was replaced with differentconcentrations of tea polyphenols solution (0.8g/L,1.6g/L and3.2g/L) when therats weights over180g. The oral glucose tolerance test (OGTT) was taken at the26thweek, and then the rats were sacrificed. The serum was separated for measurement ofserum insulin levels by ELISA and determination of blood sugar levels and bloodlipid levels by commencial kit. HOMA-IR index was calculated according to theformula. The liver, epididymal fat and perirenal fat weight, were accurately weighedand the visceral fat coefficient and liver coefficient were calculated. The fatdeposition in liver was measured by oil red O staining on frozen sections. Real-timequantitative PCR was used to detect the mRNA expression of fatty acid synthase(FAS),3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoAR), peroxisomeproliferator activated receptor α,(PPARα), sterol regulatory element bindingprotein-1c (SREBP-1c), glucose-6-phosphatase (G6Pase), phosphoenolpyruvatecarboxykinase (PEPCK) and glucose transporter2(GLUT2) in the liver..
Results: The food intake of the control group is higher than that of the other groups;however, the energy intake is equal in all groups due to the different energy density ofthe standard chow and the high fat chow. From the9th week on, the weight of high fatfed rats was significantly higher than that of the control group. At the end of theexperiment, body weight and visceral fat coefficients of high fat fed rats weresignificantly higher than that of the control group. Compared with the high-fat group,the body weight and visceral fat coefficients were significantly reduced in GTPs treated groups. High fat fed rats exhibited significantly higher blood glucose levelsthan the control group; the blood glucose of GTPs treated groups was significantlylower than that of the high-fat group. The glucose tolerance in high-fat rats was lowerand the insulin HOMA-IR index was higher than that in the control group, and GTPsintervention improved the glucose tolerance and down-regulated the HOMA-IR indexin high-fat fed rats. The serum insulin level in high-fat group is significantly higherthan that in the control group, GTPs treatment didn’t change the insulin level in highfat fed rats. High fat diet induced dyslipidemia in rats. Compare to the control group,the serum triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and totalcholesterol (TC) level was significantly increased. The serum high-density lipoproteincholesterol (HDL-C) was significantly decreased, and the LDL-C/HDL-C rationincreased significantly, all these alterations except for HDL-C levels were alleviatedby GTPs treatment to different extents. In the liver, high-fat diet induced fatdeposition, increased mRNA expression of genes related to fat synthesis (the FAS,HMG-CoAR and SREBP-1), and reduced mRNA expression of fatty acid oxidationgene, PPARα. The alterations in fat deposition and expression of genes were allalleviated by GTPs treatment. High-fat diet also significantly raised the mRNAexpression of the key and rate-limiting enzymes of gluconeogenesis (PEPCK andG6Pase), and reduced the mRNA expression of the major glucose transporter in theliver (GLUT2), these alterations in hepatic glucose metabolism gene expressionsinduced by high fat diet were also mitigated by GTPs.
Conclusion: The high-fat diet induced metabolic syndrome, fat deposition in the liverand dysregulated the hepatic mRNA expression of genes related to fat and glucosemetabolism in rats, these changes are irrelative to total energy intake. GTPs alleviatedthe high-fat diet-induced metabolic syndrome, fat deposition in the liver and abnormalhepatic mRNA expressions of glucose and lipid metabolism related genes.
Part2The Effect and cell signaling mechanism of GTPs on adiponectinproduction
Objective: The mechanism underlying the metabolism regulating effects of GTPsremains unclear. Hypoadiponectinemia plays an important role in the development ofobesity, metabolic syndrome and related diseases, and adiponectin had beenconsidered to be a new therapeutic target for treatment of obesity and insulinresistance. In this section we observed the effects of GTPs on adiponectin levels inhigh-fat fed rats and explored the possible mechanism.
Methods: Animal management was stated in part1. The serum adiponectin levelswere determined by ELISA, The mRNA expression of adiponectin and PPARγ invisceral fat of the rats were determined by real-time quantitative PCR. The proteinexpression of PPARγ, the phosphorylation of PPARγ, and protein expressionextracellular signal-regulated kinase extracellular signal regulated kinase (ERK)1/2and phosphorylated ERK1/2levels were detected by Western blot. Rat visceraladipose tissue were cultured in vitro with high glucose DMEM medium, and treated with GTPs or pretreated with PD98059, a specific inhibitor of ERK1/2pathway. After24hours intervention, the culture medium was collected and the adiponectin levels init were determined by ELISA, the cultured visceral adipose tissue were collected andthe mRNA expression of adiponectin and PPARγand protein expressions PPARγ,phosphorylated PPARγ, ERK1/2and phosphorylated ERK1/2were determined byreal-time quantitative PCR and western blot respectively.
Results: The adiponectin mRNA levels and serum adiponectin level was significantlylower in the high fat group than those in the control group, and GTPs treatmentsignificantly mitigated the decrease in adiponectin in high fat fed rats. Compared withthe control group, the ERK1/2activation and PPARγ phosphorylation in the visceralfat were increased significantly. Meanwhile, the PPARγ mRNA levels and proteinlevels were decreased significantly. Compared with the high-fat group, the activationof ERK1/2and PPARγ phosphorylation were significantly lower, and PPARγexpression levels were significantly increased. High glucose cultured visceral adiposetissue also exhibited significantly reduced mRNA and secretion levels of adiponectin,up-regulated ERK1/2and PPARγ phosphorylation levels and decreased PPARγexpression levels. GTPs intervention and ERK1/2inhibitor pretreatment bothinhibited the ERK1/2activation, PPARγphosphorylation, and raised the PPARγexpression and adiponectin expression and secretion in high glucose cultured ratvisceral adipose tissue.
Conclusion: The regulation of adiponectin levels is an important mechanismunderlying the preventive and mitigative effects of GTPs on high-fat diet-inducedmetabolic disorders. GTPs increase the adiponectin level by inhibition of ERK1/2activation, decrease the PPARγ phosphorylation and increase the level of PPARγexpression.
Part3The effects and mechanism of GTPs on vascular endothelialhyperpermeability
Objective: Atherosclerotic cardiovascular diseases, which make biggest contributionto morbidity and mortality of cardiovascular diseases, are metabolic syndromerelated diseases. Endothelial hyperpermeability, referring to increased transport oflarge molecules including AGE and lipoproteins to the subendothelial space, is theprimary reaction of endothelium to damage factors like hyperglycemia orhyperlipidemia, an early marker and one of the major performances of endothelialdysfunction, and the primary change in the development of atherosclerosis. Theobjective of this part is to observe the effect of high-fat diet on endothelialpermeability in rat aorta with the focus on effects of GTPs intervention, and toexplore the mechanisms underneath both in vivo and in vitro.
Methods: Animal management and intervention were same with part1, bovine aorticendothelial cells (BAECs) were cultured with high glucose culture medium, andtreated with GTPs (0.4, or4μg/mL.24h), or pretreated with DPI (10μM) or SU5416(10μM) pre-incubated for30min or incubated with rhVEGF (8ng/mL), beta cyclodextran intervention (8μM) for30min before the test of permeability inmonolayer bovine aortic endothelial cells. The endothelial permeability in rat aorticwas measured using Evans blue injection, and the permeability in monolayer bovineaortic endothelial cells was measured by the fluorescein isothiocyanate (FITC)-glucan assay. Dihydro-ethidium (DHE) fluorescent probe was used to detect thereactive oxygen species (ROS) level in rat aortic, the2',7'-dichloro-fluoresceindiacetate (DCFH-DA) fluorescent probe to detect ROS levels in cultured BAECs. Thereal-time quantitative PCR was used to detect the mRNA levels of vascularendothelial growth factor (VEGF) and caveolin-1. VEGF levels in serum and cellculture medium were measured by ELISA.Western blot assay was used to detect theprotein levels of cav-1, p22phox and p67phox in cultured BAECs.
Results: Compared with the control group, the high fat diet increased the endothelialpermeability in rat aorta, comparing with the high-fat group, the permeability in aortaof GTPs treated groups were significantly lower. Meanwhile, high-fat dietsignificantly increased the ROS level and the mRNA level of vascular endothelialgrowth factor (VEGF), a strong permeability factor, in the aorta and upregulated theserum level of VEGF, GTPs treatment significantly reduced the high fat diet inducedincrease in VEGF and ROS. In high glucose cultured BAECs, the endothelialpermeability, VEGF expression and secretion, ROS level were all increased. Highglucose culture also increase the expression of p22phox and p67phox subunits ofNADPH oxidase and the expression of caveolin-1, GTPs mitigated the elevatedVEGF expression and secretion, ROS increase, up-regulated expression of p22phox,p67phox and caveolin-1induced by high glucose incubation. Similar to high glucoseculture, rhVEGF treatment increased the endothelial permeability in monolayerBAECs cultured in normal DMEM. Preincubation with SU5416(VEGF receptorinhibitor), DPI (NADPH oxidase inhibitor) or treatment with β cyclodextran(structural inhibitor of caveolae) all down-regulated the endothelial permeability inhigh glucose cultured monolayer BAECs. SU5416also down-regulated the cavelin-1expression in BAECs cultured in high glucose DMEM.
Conclusion: High fat diet could induce endothelial hyperpermeability in rat aorta, andthis variation could be mitigated by GTPs treatment. GTPs regulated the endothelialpermeability in high fat rats by down-regulating NADPH oxidase, ROS production,thus decreased the VEGF levels and the expression of cav-1, which induceddown-regulation of caveolae mediated large molecule transport and alleviate theendothelial hyperpermeability.
引文
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