肾阳虚对实验大鼠血脂的影响及其机制研究
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摘要
目的：本研究立足于肾主气化的理论，以肌注氢化可的松复制肾阳虚大鼠模型为平台，观察模型大鼠的血脂变化，以肾阳虚高脂血症对LXR-α蛋白表达的影响为切入点，探讨LXR-α蛋白及其调控的JAK2/STAT3信号转导通路与肾阳虚高脂血症大鼠血脂影响的相关机制，并观察右归丸对肾阳虚模型大鼠有关血脂相应指标的影响。通过检测其TG、TC、LDL-C和HDL-C的含量，JAK2、STAT3、LXRα、SREBP-1c、FAS、ABCA1和CETP基因的mRNA及蛋白表达等相关指标的变化，旨在从LXRα蛋白表达调控细胞内的信号通路来初步阐明肾阳虚导致高脂血症的机理。
方法：采用8周龄SD大鼠60只，雄性，随机分为正常对照组、模型组和右归丸治疗组三组。除正常对照组外，其余各组大鼠每天均采用肌注氢化可的松方法复制肾阳虚大鼠模型。正常对照组大鼠每天上午8:00肌肉注射生理盐水1ml/200g体重，其余组大鼠每天上午8:00肌肉注射氢化可的松1ml/200g（药物浓度为5mg/ml），持续15天；从第16天开始，右归丸组大鼠灌胃右归丸混悬液2ml/200g（药物浓度为0.243g/ml），其余组大鼠灌胃生理盐水2ml/200g，均持续30天。所有动物在实验的第16天和第46天分别放入相应标记的代谢笼中，取24小时尿液；在第16天于尾动脉取血，第46天断头取血，然后剪开大鼠腹壁，分离肝脏，并进行相关指标检测：①检测24小时尿17-OH-CS及血清睾酮（T）的含量；②检测TG、TC、LDL-C和HDL-C的含量；③检测肝指数的变化，并观察肝组织的形态学改变；④免疫组织化学染色法检测肝组织中LXRα蛋白的表达；⑤检测大鼠肝组织JAK2、STAT3、LXRα、SREBP-1c和FASmRNA及蛋白免疫印迹法检测SREBP-1c和FAS蛋白表达。⑥检测第46天血浆中ABCA1和CETPmRNA及蛋白免疫印迹法检测ABCA1和CETP蛋白表达。
结果：
①24小时尿液及血清T含量检测结果：第16天与正常对照组比较，模型组和右归丸组大鼠尿液17-OH-CS及血清T含量显著降低（P<0.01），模型组和右归丸组比较无明显差异。第46天与正常对照组比较，模型组大鼠尿液17-OH-CS及血清T含量显著降低（P<0.01）；与模型组比较，右归丸组大鼠尿液17-OH-CS及血清T含量显著升高（P<0.01）。
②血清TG、TC、LDL-C、HDL-C含量检测结果：第16天与正常对照组比较，模型组和右归丸组大鼠血清TG、TC、LDL-C显著升高（P<0.01），HDL-C含量显著降低（P<0.01）；模型组和右归丸组比较无明显差异。第46天与正常对照组比较，模型组大鼠血清TG、TC、LDL-C显著升高（P<0.01），HDL-C含量显著降低（P<0.01）；与模型组比较，右归丸组大鼠血清TG、TC、LDL-C含量显著降低（P<0.01），HDL-C含量显著升高（P<0.01）。
③肝指数检测结果：与正常对照组比较，模型组大鼠肝指数明显增加（P<0.05），右归丸组大鼠肝指数明显增加（P<0.05）；右归丸组与模型组比较肝指数明显降低（P<0.05）。
④肝组织形态学观察结果：与正常对照组比较，模型组大鼠肝小叶结构明显紊乱，肝细胞索模糊乃至消失，肝细胞形态不均一，细胞体积增大，胞质疏松，胞浆内充满大小不一脂滴，可见部分细胞核挤向胞膜，部分细胞核溶解，汇管区炎性细胞浸润较明显，另可见散在的点状坏死灶。右归丸组大鼠肝小叶结构较完整，肝细胞排列较整齐，体积明显缩小，脂滴较模型组少，肝细胞脂肪变性明显改善，少许炎性细胞浸润。
⑤LXRα蛋白表达结果：实验大鼠免疫组化LXRα蛋白阳性反映，模型组大鼠肝组织LXRα蛋白表达最强、右归丸组有所减弱、正常组最弱。
⑥JAK2、STAT3、LXRα、SREBP-1c、FAS的mRNA表达结果：与正常对照组比较，模型组大鼠肝组织JAK2、STAT3、LXRα、SREBP-1c、FAS的mRNA的表达水平显著升高（P＜0.01）；右归丸组JAK2、STAT3、LXRα、SREBP-1c、FASmRNA的表达水平明显升高（P＜0.05）；但右归丸组较模型组JAK2、STAT3、LXRα、SREBP-1c、FASmRNA的表达水平显著降低（P＜0.01）。对大鼠肝组织SREBP-1c和FAS蛋白表达结果显示：模型组的灰度值最大，胶片的条带最粗，蛋白表达最强，其次为右归丸组，再次为正常组，灰度值最小，胶片的条带最细，蛋白表达最弱。
⑦ABCA1、CETP的mRNA的表达结果：与正常对照组比，模型组大鼠血浆中ABCA1和CETP的mRNA的表达水平显著升高（P＜0.01）；右归丸组ABCA1和CETPmRNA的表达水平明显升高（P＜0.05）；但右归丸组较模型组ABCA1和CETPmRNA的表达水平显著降低（P＜0.01）。大鼠血浆中ABCA1和CETP蛋白表达结果显示：模型组的灰度值最大，胶片的条带最粗，蛋白表达最强，其次为右归丸组，再次为正常组，灰度值最小，胶片的条带最细，蛋白表达最弱。
结论：
①采用肌注氢化可的松复制肾阳虚大鼠模型，模型大鼠的一般情况，及模型大鼠24小时尿17-OH-CS和血清T含量明显降低都符合肾阳虚证的诊断标准，同时血清TG、TC、LDL-C含量明显升高，HDL-C含量明显降低，表明肾阳虚高脂血症大鼠模型复制成功。
②高脂血症可以导致肝组织脂类代谢障碍，并出现形态学改变。
③温补肾阳方药——右归丸可以抑制机体JAK2、STAT3、LXRα、SREBP-1c和FAS的表达，减少甘油三酯的合成。
④温补肾阳方药——右归丸可以通过下调JAK2、STAT3、LXRα、ABCA1和CETP的表达，减少胆固醇在血浆中的沉积，促进胆固醇入肝脏代谢。
本研究首次采用肌注氢化可的松方法成功复制出肾阳虚高脂血症大鼠模型，率先提出肾阳虚是高脂血症的主要病机；实验研究发现，肾阳虚激活了模型大鼠肝组织中的JAK2/STAT3通路，使其LXRα蛋白过度表达，进而使其下游的SREBP-1c和FAS以及ABCA1和CETP蛋白表达增多，从而使机体血清中TG和TC含量显著增高，因而形成高脂血症；温补肾阳方药——右归丸可以显著降低LXRα蛋白的表达，从而改善模型大鼠的高血脂状态。由此推知，右归丸调节血脂代谢、纠正血脂紊乱的机制可能是通过抑制LXRα蛋白的过度表达而实现的。
Objects: This research based on the kidney’s main function is gasification,using the intramuscular injection of hydrocortisone established deficiency ofkidney-yang animal models as a platform, to observe the changes of bloodlipid of the rats with kidney yang deficiency, effects of hyperlipidemia on theexpression of LXR-α protein as the breakthrough point, study of themechanism of lipid in JAK2/STAT3signal transduction pathway anddeficiency of Kidney Yang high hyperlipidemia rats LXR-α protein and itsregulation and control, and to observe the effect of Yougui Pill on kidney yangdeficiency model rats blood lipid indexes related to. By detecting the contentof its TG, TC, LDL-C and HDL-C, JAK2, STAT3, changes of LXR α,SREBP-1c, FAS,ABCA1and CETP gene mRNA and protein expression, inorder to LXRα expression pathway within the cell to elucidate the mechanismof kidney yang deficiency syndrome in hyperlipemia.
Methods: This study was performed at8weeks of age of60SD rats, male,were randomly divided into normal control group, model group and YouguiPill Treatment Group. Except the normal control group, the remaining ratswere intramuscular injection of hydrocortisone method to copy the rat modelof kidney yang deficiency. The rats in the normal control group every morning8:00intramuscular injection of physiological saline1ml/200g weight, the restrats at8:00intramuscular injection of hydrocortisone1ml/200g (drug concentration was5mg/ml), lasted15days; at the sixteenth day, Yougui Pillgroup gavage Yougui Pill suspension2ml/200g (drug concentration was0.243g/ml), the other group of rats physiological saline2ml/200g, which hadbeen lasted for30days. All animal in experiment sixteenth and forty-sixthdays were placed in metabolic cages in the corresponding markers,24hoururine; at the sixteenth day and blood samples were collected from the tailartery,at forty-sixth day to complete the animal with the sampling blood, thencut open the abdominal wall, isolated from rat liver, and associated indicatorsdetection:①detecting24urinary17-OH-CS and serum testosterone (T)content;②the detection of TG, TC content, LDL-C and HDL-C;③changedetection index of the liver, and to observe the change of structure of livertissues;④the immunohistochemical staining method was used to detect theexpression of LXRα protein in liver tissue;⑤the detection expression ofJAK2STAT3, LXRα, SREBP-1c and FAS mRNA in liver tissue of rats andimmunoblot assay for detection of SREBP-1c and FAS；⑥the detectionmRNA expression of ABCA1and CETP in the plasma of rats on the46th day,and immunoblot assay for detection of ABCA1and CETP；
Results:①24hours urine and Testosteron: At the sixteenth day,comparingwith the normal control group, the model group and the Yougui Pill group ratswhich of urinary17-OH-CS and T was significant decreased（P<0.01）,butthere was not any significant differences in the model group and the YouguiPill group. At the forty-sixth day,comparing with the normal control group, themodel group was still significant decreased（P<0.01）,but comparing with themodel control group, the Yougui Pill group rats were dramatically increased（P<0.01）.②serum indicators testing: At the sixteenth day, comparing withthe normal control group, the model group and the Yougui Pill group ratswhich of TG、TC、LDL-C were significant increased（P<0.01）, in the contentof HDL-C was significant decreased （P<0.01）.,but there was not any significant differences in the model group and the Yougui Pill group; At theforty-sixth day,comparing with the model control group, the Yougui Pill grouprats in the content of TG、TC、LDL-C were dramatically decreased（P<0.01）,the HDL-C was dramatically increased（P<0.01）;③the liver index testing:compare with the normal control group, the model group and the Yougui Pillgroup rats whice of the liver index was were obviously increased（P<0.05）,compare with the model control group, the Youguiwan group rats wereobviously decreased（P<0.05）; Light microscopy showed: comparison of thenormal control group,the model group rats were significantly disorder in thehepatic lobule structure and liver cell cord fuzzy or even disappear, liver cellmorphological heterogeneity, cell volume increases, cytoplasm rarefaction, thecytoplasm is full of different sizes of lipid droplets, visible part of the nucleusis squeezed to the cell membrane, some nucleus were dissolved.In the portalarea the inflammatory cell was obvious, and focal necrosis were seen scatteredin the other. The structure of hepatic lobule Yougui Pill group rats were intact,liver cells were arranged in order, reduce the size, lipid droplets less than themodel group, fatty degeneration of liver cells is significantly improved,andhad a little inflammatory cell;④the LXR-α protein by immunohistochemistry methods showed: model LXR α protein in liver of rat was strongest,Yougui Pill group, the normal group was weakened.⑤Detection of theexpression of related gene index in the liver: compare with the normal controlgroup, the model group rats whice of JAK2、STAT3、LXRα、SREBP-1c andFAS mRNA expression had dramatically increased（P<0.01）,the Yougui Pillgroup had obviously increased（P<0.05）;but compare with the model controlgroup, the Yougui Pill group rats had dramatically decreased（P<0.01）;SREBP-1c and FAS in Western blotting showed: The maximum value of graywas the model group, which the film with the most coarse, protein expressionwas the strongest, followed by Yougui Pill group, once again into the normal group, the minimum gray value, the film strip the fine and protein expression.⑥Results the mRNA expression of ABCA1and CETP: compared with normalcontrol group, the expression level of ABCA1and CETP in the plasma of therats in the model group was significantly increased in mRNA (P <0.01); theexpression level of ABCA1and CETPmRNA Yougui Pill group increasedsignificantly (P <0.05); but the expression level of Yougui Pill group than inmodel group and ABCA1CETPmRNA significantly decreased (P <0.01).The results showed that the expression of ABCA1and CETP protein inplasma of rats in model group: gray value maximum, the film with the mostcoarse, protein expression was strongest, followed by Yougui Pill group, onceagain into the normal group, the minimum gray value, the film with the mostfine, protein expression.
Conclusion:①By intramuscular injection of hydrocortisone replicatedkidney-yang deficiency rat model, general model rats accorded with thediagnostic standard of kidney yang deficiency rat model, and24hour urine17-OH-CS, in the serum TG, TC, LDL-C were increased, HDL-C wasdecreased, which showed that kidney-yang deficiency induced hyperlipidemiarat model was duplicated successfully.
②Hyperlipidemia directly lead to disorder lipid metabolism of liver andmorphological changes.
③Yougui Pill inhibited JAK2, STAT3, LXR α, SREBP-1c, FAS pathway toreduce triglyceride synthesis.
④Yougui Pill was to be down-regulation of JAK2, STAT3, LXRα,ABCA1and CETP to reduce the deposition of cholesterol in plasma cholesterol,promote the metabolism of liver.
This is the first study by intramuscular injection of hydrocortisone methodto replicate the success of the kidney-yang deficiency rats model ofhyperlipidemia, using the tonifying kidney drug--Yougui Pill can reduce hyperlipidemia in the deficiency of kidney-yang.The kidney-yang deficiencyinduced to hyperlipidemia model rats by inhibiting of adrenal corticalhormone of large dose of hydrocortisone function, and activating of theJAK2/STAT3pathway, the LXRα expression, and the expression of itsdownstream of SREBP-1c, increased FAS,ABCA1and CETP protein, so thatthe TG and TC content in serum increased significantly. Accordingly, themechanism of Yougui Pill regulating blood lipid metabolism, lipid disorderscorrection may be achieved by inhibiting the overexpression of LXRα protein.
方法：采用8周龄SD大鼠60只，雄性，随机分为正常对照组、模型组和右归丸治疗组三组。除正常对照组外，其余各组大鼠每天均采用肌注氢化可的松方法复制肾阳虚大鼠模型。正常对照组大鼠每天上午8:00肌肉注射生理盐水1ml/200g体重，其余组大鼠每天上午8:00肌肉注射氢化可的松1ml/200g（药物浓度为5mg/ml），持续15天；从第16天开始，右归丸组大鼠灌胃右归丸混悬液2ml/200g（药物浓度为0.243g/ml），其余组大鼠灌胃生理盐水2ml/200g，均持续30天。所有动物在实验的第16天和第46天分别放入相应标记的代谢笼中，取24小时尿液；在第16天于尾动脉取血，第46天断头取血，然后剪开大鼠腹壁，分离肝脏，并进行相关指标检测：①检测24小时尿17-OH-CS及血清睾酮（T）的含量；②检测TG、TC、LDL-C和HDL-C的含量；③检测肝指数的变化，并观察肝组织的形态学改变；④免疫组织化学染色法检测肝组织中LXRα蛋白的表达；⑤检测大鼠肝组织JAK2、STAT3、LXRα、SREBP-1c和FASmRNA及蛋白免疫印迹法检测SREBP-1c和FAS蛋白表达。⑥检测第46天血浆中ABCA1和CETPmRNA及蛋白免疫印迹法检测ABCA1和CETP蛋白表达。
结果：
①24小时尿液及血清T含量检测结果：第16天与正常对照组比较，模型组和右归丸组大鼠尿液17-OH-CS及血清T含量显著降低（P<0.01），模型组和右归丸组比较无明显差异。第46天与正常对照组比较，模型组大鼠尿液17-OH-CS及血清T含量显著降低（P<0.01）；与模型组比较，右归丸组大鼠尿液17-OH-CS及血清T含量显著升高（P<0.01）。
②血清TG、TC、LDL-C、HDL-C含量检测结果：第16天与正常对照组比较，模型组和右归丸组大鼠血清TG、TC、LDL-C显著升高（P<0.01），HDL-C含量显著降低（P<0.01）；模型组和右归丸组比较无明显差异。第46天与正常对照组比较，模型组大鼠血清TG、TC、LDL-C显著升高（P<0.01），HDL-C含量显著降低（P<0.01）；与模型组比较，右归丸组大鼠血清TG、TC、LDL-C含量显著降低（P<0.01），HDL-C含量显著升高（P<0.01）。
③肝指数检测结果：与正常对照组比较，模型组大鼠肝指数明显增加（P<0.05），右归丸组大鼠肝指数明显增加（P<0.05）；右归丸组与模型组比较肝指数明显降低（P<0.05）。
④肝组织形态学观察结果：与正常对照组比较，模型组大鼠肝小叶结构明显紊乱，肝细胞索模糊乃至消失，肝细胞形态不均一，细胞体积增大，胞质疏松，胞浆内充满大小不一脂滴，可见部分细胞核挤向胞膜，部分细胞核溶解，汇管区炎性细胞浸润较明显，另可见散在的点状坏死灶。右归丸组大鼠肝小叶结构较完整，肝细胞排列较整齐，体积明显缩小，脂滴较模型组少，肝细胞脂肪变性明显改善，少许炎性细胞浸润。
⑤LXRα蛋白表达结果：实验大鼠免疫组化LXRα蛋白阳性反映，模型组大鼠肝组织LXRα蛋白表达最强、右归丸组有所减弱、正常组最弱。
⑥JAK2、STAT3、LXRα、SREBP-1c、FAS的mRNA表达结果：与正常对照组比较，模型组大鼠肝组织JAK2、STAT3、LXRα、SREBP-1c、FAS的mRNA的表达水平显著升高（P＜0.01）；右归丸组JAK2、STAT3、LXRα、SREBP-1c、FASmRNA的表达水平明显升高（P＜0.05）；但右归丸组较模型组JAK2、STAT3、LXRα、SREBP-1c、FASmRNA的表达水平显著降低（P＜0.01）。对大鼠肝组织SREBP-1c和FAS蛋白表达结果显示：模型组的灰度值最大，胶片的条带最粗，蛋白表达最强，其次为右归丸组，再次为正常组，灰度值最小，胶片的条带最细，蛋白表达最弱。
⑦ABCA1、CETP的mRNA的表达结果：与正常对照组比，模型组大鼠血浆中ABCA1和CETP的mRNA的表达水平显著升高（P＜0.01）；右归丸组ABCA1和CETPmRNA的表达水平明显升高（P＜0.05）；但右归丸组较模型组ABCA1和CETPmRNA的表达水平显著降低（P＜0.01）。大鼠血浆中ABCA1和CETP蛋白表达结果显示：模型组的灰度值最大，胶片的条带最粗，蛋白表达最强，其次为右归丸组，再次为正常组，灰度值最小，胶片的条带最细，蛋白表达最弱。
结论：
①采用肌注氢化可的松复制肾阳虚大鼠模型，模型大鼠的一般情况，及模型大鼠24小时尿17-OH-CS和血清T含量明显降低都符合肾阳虚证的诊断标准，同时血清TG、TC、LDL-C含量明显升高，HDL-C含量明显降低，表明肾阳虚高脂血症大鼠模型复制成功。
②高脂血症可以导致肝组织脂类代谢障碍，并出现形态学改变。
③温补肾阳方药——右归丸可以抑制机体JAK2、STAT3、LXRα、SREBP-1c和FAS的表达，减少甘油三酯的合成。
④温补肾阳方药——右归丸可以通过下调JAK2、STAT3、LXRα、ABCA1和CETP的表达，减少胆固醇在血浆中的沉积，促进胆固醇入肝脏代谢。
本研究首次采用肌注氢化可的松方法成功复制出肾阳虚高脂血症大鼠模型，率先提出肾阳虚是高脂血症的主要病机；实验研究发现，肾阳虚激活了模型大鼠肝组织中的JAK2/STAT3通路，使其LXRα蛋白过度表达，进而使其下游的SREBP-1c和FAS以及ABCA1和CETP蛋白表达增多，从而使机体血清中TG和TC含量显著增高，因而形成高脂血症；温补肾阳方药——右归丸可以显著降低LXRα蛋白的表达，从而改善模型大鼠的高血脂状态。由此推知，右归丸调节血脂代谢、纠正血脂紊乱的机制可能是通过抑制LXRα蛋白的过度表达而实现的。
Objects: This research based on the kidney’s main function is gasification,using the intramuscular injection of hydrocortisone established deficiency ofkidney-yang animal models as a platform, to observe the changes of bloodlipid of the rats with kidney yang deficiency, effects of hyperlipidemia on theexpression of LXR-α protein as the breakthrough point, study of themechanism of lipid in JAK2/STAT3signal transduction pathway anddeficiency of Kidney Yang high hyperlipidemia rats LXR-α protein and itsregulation and control, and to observe the effect of Yougui Pill on kidney yangdeficiency model rats blood lipid indexes related to. By detecting the contentof its TG, TC, LDL-C and HDL-C, JAK2, STAT3, changes of LXR α,SREBP-1c, FAS,ABCA1and CETP gene mRNA and protein expression, inorder to LXRα expression pathway within the cell to elucidate the mechanismof kidney yang deficiency syndrome in hyperlipemia.
Methods: This study was performed at8weeks of age of60SD rats, male,were randomly divided into normal control group, model group and YouguiPill Treatment Group. Except the normal control group, the remaining ratswere intramuscular injection of hydrocortisone method to copy the rat modelof kidney yang deficiency. The rats in the normal control group every morning8:00intramuscular injection of physiological saline1ml/200g weight, the restrats at8:00intramuscular injection of hydrocortisone1ml/200g (drug concentration was5mg/ml), lasted15days; at the sixteenth day, Yougui Pillgroup gavage Yougui Pill suspension2ml/200g (drug concentration was0.243g/ml), the other group of rats physiological saline2ml/200g, which hadbeen lasted for30days. All animal in experiment sixteenth and forty-sixthdays were placed in metabolic cages in the corresponding markers,24hoururine; at the sixteenth day and blood samples were collected from the tailartery,at forty-sixth day to complete the animal with the sampling blood, thencut open the abdominal wall, isolated from rat liver, and associated indicatorsdetection:①detecting24urinary17-OH-CS and serum testosterone (T)content;②the detection of TG, TC content, LDL-C and HDL-C;③changedetection index of the liver, and to observe the change of structure of livertissues;④the immunohistochemical staining method was used to detect theexpression of LXRα protein in liver tissue;⑤the detection expression ofJAK2STAT3, LXRα, SREBP-1c and FAS mRNA in liver tissue of rats andimmunoblot assay for detection of SREBP-1c and FAS；⑥the detectionmRNA expression of ABCA1and CETP in the plasma of rats on the46th day,and immunoblot assay for detection of ABCA1and CETP；
Results:①24hours urine and Testosteron: At the sixteenth day,comparingwith the normal control group, the model group and the Yougui Pill group ratswhich of urinary17-OH-CS and T was significant decreased（P<0.01）,butthere was not any significant differences in the model group and the YouguiPill group. At the forty-sixth day,comparing with the normal control group, themodel group was still significant decreased（P<0.01）,but comparing with themodel control group, the Yougui Pill group rats were dramatically increased（P<0.01）.②serum indicators testing: At the sixteenth day, comparing withthe normal control group, the model group and the Yougui Pill group ratswhich of TG、TC、LDL-C were significant increased（P<0.01）, in the contentof HDL-C was significant decreased （P<0.01）.,but there was not any significant differences in the model group and the Yougui Pill group; At theforty-sixth day,comparing with the model control group, the Yougui Pill grouprats in the content of TG、TC、LDL-C were dramatically decreased（P<0.01）,the HDL-C was dramatically increased（P<0.01）;③the liver index testing:compare with the normal control group, the model group and the Yougui Pillgroup rats whice of the liver index was were obviously increased（P<0.05）,compare with the model control group, the Youguiwan group rats wereobviously decreased（P<0.05）; Light microscopy showed: comparison of thenormal control group,the model group rats were significantly disorder in thehepatic lobule structure and liver cell cord fuzzy or even disappear, liver cellmorphological heterogeneity, cell volume increases, cytoplasm rarefaction, thecytoplasm is full of different sizes of lipid droplets, visible part of the nucleusis squeezed to the cell membrane, some nucleus were dissolved.In the portalarea the inflammatory cell was obvious, and focal necrosis were seen scatteredin the other. The structure of hepatic lobule Yougui Pill group rats were intact,liver cells were arranged in order, reduce the size, lipid droplets less than themodel group, fatty degeneration of liver cells is significantly improved,andhad a little inflammatory cell;④the LXR-α protein by immunohistochemistry methods showed: model LXR α protein in liver of rat was strongest,Yougui Pill group, the normal group was weakened.⑤Detection of theexpression of related gene index in the liver: compare with the normal controlgroup, the model group rats whice of JAK2、STAT3、LXRα、SREBP-1c andFAS mRNA expression had dramatically increased（P<0.01）,the Yougui Pillgroup had obviously increased（P<0.05）;but compare with the model controlgroup, the Yougui Pill group rats had dramatically decreased（P<0.01）;SREBP-1c and FAS in Western blotting showed: The maximum value of graywas the model group, which the film with the most coarse, protein expressionwas the strongest, followed by Yougui Pill group, once again into the normal group, the minimum gray value, the film strip the fine and protein expression.⑥Results the mRNA expression of ABCA1and CETP: compared with normalcontrol group, the expression level of ABCA1and CETP in the plasma of therats in the model group was significantly increased in mRNA (P <0.01); theexpression level of ABCA1and CETPmRNA Yougui Pill group increasedsignificantly (P <0.05); but the expression level of Yougui Pill group than inmodel group and ABCA1CETPmRNA significantly decreased (P <0.01).The results showed that the expression of ABCA1and CETP protein inplasma of rats in model group: gray value maximum, the film with the mostcoarse, protein expression was strongest, followed by Yougui Pill group, onceagain into the normal group, the minimum gray value, the film with the mostfine, protein expression.
Conclusion:①By intramuscular injection of hydrocortisone replicatedkidney-yang deficiency rat model, general model rats accorded with thediagnostic standard of kidney yang deficiency rat model, and24hour urine17-OH-CS, in the serum TG, TC, LDL-C were increased, HDL-C wasdecreased, which showed that kidney-yang deficiency induced hyperlipidemiarat model was duplicated successfully.
②Hyperlipidemia directly lead to disorder lipid metabolism of liver andmorphological changes.
③Yougui Pill inhibited JAK2, STAT3, LXR α, SREBP-1c, FAS pathway toreduce triglyceride synthesis.
④Yougui Pill was to be down-regulation of JAK2, STAT3, LXRα,ABCA1and CETP to reduce the deposition of cholesterol in plasma cholesterol,promote the metabolism of liver.
This is the first study by intramuscular injection of hydrocortisone methodto replicate the success of the kidney-yang deficiency rats model ofhyperlipidemia, using the tonifying kidney drug--Yougui Pill can reduce hyperlipidemia in the deficiency of kidney-yang.The kidney-yang deficiencyinduced to hyperlipidemia model rats by inhibiting of adrenal corticalhormone of large dose of hydrocortisone function, and activating of theJAK2/STAT3pathway, the LXRα expression, and the expression of itsdownstream of SREBP-1c, increased FAS,ABCA1and CETP protein, so thatthe TG and TC content in serum increased significantly. Accordingly, themechanism of Yougui Pill regulating blood lipid metabolism, lipid disorderscorrection may be achieved by inhibiting the overexpression of LXRα protein.
引文
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