【作者】 刘丰；

【导师】 刘莉；

【作者基本信息】 黑龙江中医药大学 ， 内科学， 2009， 博士

【摘要】 目的：观察加减黄连温胆汤对膳食诱导的MS大鼠的干预作用，并以脂肪细胞因子和内皮功能为切入点探讨该药作用的分子机制。方法：雄性SD大鼠60只随机分为两组，正常组10只，实验组50只，分别予普通饲料和高脂高糖高盐饲料饲喂20周。成模的37只MS大鼠，随机分为模型组、加减黄连温胆汤高、低剂量组，二甲双胍对照组、灌服相应药物4周。动态测量体重、血压、空腹血糖、FINS、血脂等指标，计算HOMA-IR，进行模型及药物作用评价。药物干预前后观察各组大鼠主动脉病理变化（HE染色法），采用ELASA法测量各组大鼠血清vWF因子；放免法检测血清脂肪酸、瘦素、肿瘤坏死因子、白介素-6、脂联素水平；RT-PCR检测脂肪组织脂联素mRNA的表达。结果：饲喂20周末，实验组大鼠体重、腹围、Lee′s指数、血压、空腹血糖、空腹胰岛素、HOMA-I R、血脂TG、TC以及LDL均明显增高，HDL水平减低，与正常组比较，经统计学分析，有显著性差异（P＜0．01）。药物干预4周末，与模型组比较，加减黄连温胆汤高、低剂量组及二甲双胍组体重、血压均下降，其中加减黄连温胆汤高剂量组与二甲双胍组体重下降（P＜0．01）。加减黄连温胆汤高剂量组大鼠血压明显下降，与模型组比较有统计学意义（P＜0．05）。加减黄连温胆汤高剂量和二甲双胍组大鼠血糖出现不同程度下降(P_高＜0．05，P_二甲＜0．0 1)；加减黄连温胆汤高剂量组大鼠TG、TC和LDL-C水平均与模型组比较有显著性差异（P＜0．01）；加减黄连温胆汤高剂量组和二甲双胍组大鼠FINS水平均较模型组降低(P_二甲＜0．01，P_高＜0．05)；加减黄连温胆汤高剂量组和二甲双胍组大鼠胰岛素抵抗指数均下降，有显著性差异（P＜0．01）；加减黄连温胆汤高剂量组和二甲双胍组大鼠Lee’s指数、内脏脂肪重量及内脏脂肪与体重的比值均明显降低，有显著性差异（P＜0．01）。主动脉H染色显示，MS模型组大鼠主动脉存在严重的内皮损伤；加减黄连温胆汤高剂量组、低剂量组、二甲双胍组有不同程度改善，以加减黄连温胆汤高剂量组改善最明显；与正常组比较，MS模型组血清vWF水平明显升高（P＜0．01），与MS模型组相比，加减黄连温胆汤高、低剂量组vWF水平均明显降低（P＜0．01）。与空白组比较，MS模型组血清FFA、瘦素、TNF-α、IL-6水平升高（P＜0．01）。药物干预4周末，与MS模型组相比，加减黄连温胆汤高、低剂量组、二甲双胍组FFA水平均明显降低（P＜0．01）；加减黄连温胆汤高剂量和二甲双胍组大鼠血清瘦素、TNF-α、IL-6浓度降低（P＜0．01）；与空白组相比，模型组ADPN水平和脂联素mRNA相对定量基因表达显著减低（P＜0．01）；与模型组比较，加减黄连温胆汤高剂量和二甲双胍组ADPN水平增高（P＜0．05）；加减黄连温胆汤高剂量组ADPN mRNA相对定量基因表达升高（P＜0．01）；二甲双胍组ADPN mRNA无显著性差异（P＞0．05）。结论：1．长期高脂高糖高盐饮食饲喂SD大鼠可成功复制MS大鼠模型，并且该模型具备人类MS的基本临床特征。2．加减黄连温胆汤具有减重、降压、调脂、改善胰岛素抵抗作用，能够改善MS各组分，综合疗效优于二甲双胍，是防治MS的有效药物，值得进一步研究开发3．MS大鼠存在内皮功能损伤，加减黄连温胆汤能降低血清vWF水平，改善MS大鼠主动脉组织结构，对血管内皮功能损伤具有改善作用。4．加减黄连温胆汤具有降低MS大鼠血清TNF-α、IL-6水平，抑制炎症反应的作用。5．加减黄连温胆汤能够降低MS大鼠血清FFA、瘦素、脂联素水平，促进脂联素mRNA表达，具有调节脂肪细胞因子的作用。6．黄连温胆汤能够调节脂肪细胞因子表达、抑制炎症反应，这可能是该药改善MS血管内皮功能的机制之一。更多还原

【Abstract】 Objective:To observe the effect of huanglianwendan decoction onmetabolic syndrome food-inducing rats,and Start with adipocyto-kines andendodermis function to discuss the molecular mechanism thathuanglianwendan decoction prevents and treats MS.Method:Sixty 8-week-old male SD rats were randomly divided into 2groups which are vacuity group (n=10)and experimental group (n=50)vacuity group was fed with common diet,and experimental group was fedwith high lipid,high salt and high glucose diet for 20 weeks to induceexperimental metabolic syndrome.37 SD rats in experimental group whichwere modeled successfully were randomly divided into 4 groups:modelgroup huanglianwendan decoction high-dose group,low-dose group andMetformin Hydrochioride control group,which were lavaged with theappropriate drug for 4 weeks.Dynamic state measure weight,blood pressure,fasting blood glucose,serum insulin,lipids and other indicators,calculateHOMA-IR,to evaluate model and drug effect.Before and after drug therapy,we observed the pathological change of aorta by HE staining method,andtested:the vWF factor levels of serum by ELISA method;the level of FFA,LEP,TNF-α,IL-6 and ADPN in serum by RIA method;the expressions ofADPNmRNA in adipose tissue by RT-PCR method in each group.Result:After feeding for 20 weeks,the weight,abdominalcircumference,Lee’s index,blood pressure,fasting glucose,fasting insulin,HOMA-IR,lipids TG,TC and LDL of Experimental rats were significantlyhigher,HDL level of reduction,compared with the vacuity group,thedifference was significant (P＜0.01).After 4 weeks treated with drugs,compared with the model group,theweight and blood pressure decreased in huanglianwendan decoction high andlow-dose group and the metformin group,in which huanglianwendandecoction high-dose group and metformin group weight loss significantly (P＜0.01).The blood pressure in Huanglianwendan Decoction high-dose groupdecreased obviously,compared with the model group,it was statisticallysignificant (P＜0.05).the blood glucose of huanglianwendan decoctionhigh-doses group and metformin group decreased with varying degrees (P＜0.01),(P＜0.05)Compared with the model group,there were remarkabledifferentce In the TG,TC and LDL-C level of huanglianwendan decoctionhigh doses group P＜0.01).The serum insulin levels of huanglianwendan decoction high-dose group and metformin group were lower than those inmodel group (P＜0.01),(P＜0.05).The insulin resistance index(HOMA-IR)in huanglianwendan decoction high-dose group and the metformin groupdecreased,and there was significantly difference (P＜0.01).The Lee’s index,visceral fat weight,visceral fat and body weight ratio in huanglianwendandecoction high-dose group and the metformin group were significantlydecreased,the difference was remarkable (P＜0.01).The MS model group rats had serious endothelial injury in aortic Hstaining;huanglianwendan decoction high-dose group,low-dose group andmetformin group,there are amelioration in endothelial injury with varyingdegrees;the huanglianwendan decoction high-dose group had the mostobvious amelioration.Compared with the vacuity group,the serum vWFlevels of MS model group were significantly higher (P＜0.01),comparedwith the MS model,the vWF level in huanglianwendan decoction high andlow dose group were lower significantly (P＜0.01).Serum FFA,leptin,TNF-αand IL-6 concentration in MS model groupincreased,Compared with the vacuity group,the difference was obvious (P＜0.01);compared with the model group,the FFA level in the other threegroup decreased remarkably.serum leptin,TNF-α,IL-6 concentrations ofhuanglianwendan decoction high-dose group and metformin group ratsdecreased (P＜0.01).Compared with the vacuity group,the ADPN level landrelative quantitative gene expression of ADPNmRNA in model groupsignificantly reduced (P＜0.01);compared with the model group,the ADPNlevel of huanglianwendan decoction high-dose group and metformin groupincreased (P＜0.05);the relative quantitative gene expression of ADPNmRNA in huanglianwendan decoction high-dose group increased,(P＜0.01).the relative quantitative gene expression of ADPN mRNA in Metformingroup had no significant difference (P＞0.05).Conclusion:1.High fat high sugar high salt diet feeding SD rats forLong term can copy the MS model with the basic human clinical features ofMS.2.Huanglianwendan Decoction can loss weight,lower blood pressure,regulate lipid and improve insulin resistance,which can improve the variouscomponents of MS.The comprehensive effect of huanglianwendan decoctionis superior than that of metformin.Huanglianwendan decoction is aneffective drug on preventing and treating MS,which has the value to researchand develope further. 3.there is endothelial dysfunction in MS rats,but huanglianwendandecoction can reduce the level of serum vWF and improve the organizationalstructure of the MS rat aorta to improve vascular endothelial dysfunction.4.Huanglianwendan decoction has the effect on reducing serum TNF-α,IL-6 levels of MS rats and inhibiting inflammatory response.5.Huanglianwendan decoction can reduce the levels of FFA,leptin andadiponectin in the MS rats serum and promote the expression of adiponectinmRNA,which has obvious effect of regulating adipocytokines.6.Huanglianwendan decoction can regulate the expression ofadipocyto-kines and inhibit inflammatory response,which may be one of themechanisms to improve vascular endothelial function in MS.更多还原