小鼠高脂性脂肪肝模型的建立及盐酸千金藤碱对其治疗作用的研究
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摘要
背景和目的：
高脂性脂肪肝是非酒精性脂肪肝的一种类型,它从单纯性脂肪变性可能发展为脂肪性肝炎、肝纤维化甚至肝硬化。高脂性脂肪肝的高发病率越来越引起人们的重视。积极研发其治疗的理想药物意义重大。本课题探讨建立小鼠高脂性脂肪肝动物模型的方法,并观察盐酸千金藤碱(CH)对该模型的治疗作用,尤其是对该模型小鼠脂代谢和脂质过氧化机制方面的影响。
材料与方法：
(1)分别观察三种脂肪肝动物模型：四氯化碳、地塞米松加高脂饮食、酒精所致小鼠脂肪肝模型血脂的变化,检测小鼠血脂水平和转氨酶活性,以筛选表现高脂血症的动物模型。
(2)通过腹腔注射地塞米松的同时灌服高脂乳剂复制小鼠高脂性脂肪肝模型,检测小鼠血脂及肝脂水平,同时进行肝脏组织病理学检查,进一步确定小鼠高脂性脂肪肝模型的建立。
(3)复制地塞米松和高脂饮食所致的小鼠高脂性脂肪肝模型,应用不同剂量CH对其进行治疗,并以注射用硫普罗宁为阳性对照药,检测小鼠血脂及肝脂水平、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性、丙二醛(MDA)含量等指标,同时进行肝脏病理组织切片观察小鼠肝脏细胞改善情况。
结果：
(1)与正常对‘照组相比,四氯化碳模型组血清中丙氨酸转氨酶(ALT)天冬氨酸转氨酶(AST)活性显著升高(P<0.01),血脂甘油三酯(TG)及总胆固醇(TC)没有统计学差异；地塞米松模型组血清中两种转氨酶活性和血脂都显著性升高(P<0.01)；酒精模型组血清ALT活性显著升高(P<0.01),其他三项指标无显著性差异。
(2)与正常对照组相比,小鼠脂肪肝模型组血清中TG、TC、ALT、AST均显著性升高(P<0.01),肝匀浆中TG、TC含量及肝脏指数亦显著性增高(P<0.01),病理检查可见肝组织脂肪变性及炎性浸润,表明成功建立小鼠高脂性脂肪肝模型。
(3)与对照组相比,模型组小鼠血清TG、TC、ALT、AST活性和肝组织TG、TC、MDA含量显著升高(P<0.01),肝组织SOD和GSH-Px活性显著降低(P<0.01),以及肝脏病理组织学检查均表明成功建立了小鼠高脂性脂肪肝模型。CH高剂量组小鼠血清TG、TC、ALT、AST及肝组织TG、TC、MDA显著低于模型组(P<0.01或P<0.05),肝组织SOD和GSH-Px活性显著高于模型组(P<0.01)；通过大体标本和肝脏病理学检查得知,不同剂量CH均能改善肝细胞脂肪变性情况,以高剂量组最为明显。
结论：
(1)三种模型中,地塞米松加高脂饮食所致脂肪肝小鼠模型中同时存在血脂代谢紊乱及肝脏损伤,值得进一步全面评价。
(2)成功建立地塞米松和高脂饮食所致的小鼠高脂性脂肪肝模型。
(3)CH对地塞米松和高脂饮食所致的小鼠高脂性脂肪肝具有良好的治疗作用,其机制可能与其能够提高抗氧化酶活性、抑制脂质过氧化反应等方面有关。
Background&Purpose:
Hyperlipidemic fatty liver disease (HFLD) is one kind of non-alcoholic fatty liver disease. The simple steatosis may develop to steatohepatitis, liver fibrosis or cirrhosis. It is caused more attention by the high incidence. It is of great significance to develop the ideal drug to treat HFLD. To study and establish the animal model of hyperlipidemic fatty liver in mice and to observe the therapeutic effects of Cepharanthine Hydrochloride (CH) against the models induced by Dexamethasone (DEX) and high-fat diet in mice.
Materials and methods:
1 Three fatty liver animal models were produced by carbon tetrachloride (CTC), DEX and alcohol (ALC). The total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), aspartate amintransferase (AST) in the serum were measured.
2 Hyperlipidemic fatty liver model (HFLM) was produced by injecting Dexamethasone Sodium Phosphate injection in the mice'abdomen and feeding mice high-fat diet at one time. The TC, TG, ALT, AST in the serum and the TC, TG in the liver were measured. Liver tissues were observed with optical microscope.
3 The hyperlipidemic fatty liver mice models were prevented with different doses (low, middle and high) contrasting with Tiopronin. The TC, TG, ALT, AST in the serum and the TC, TG, superoxide dismutase (SOD), maeic dialdehyde (MDA), glutathion peroxidase (GSH-Px) in the liver were measured. Liver tissues were observed.
Results:
1 Compared with the normal control group, the activations of ALT and AST were increased significantly (p<0.01), TG and TC were no significant difference in the CTC group; The TC, TG, ALT and AST in the serum were increased significantly in DEX group (p<0.01); the activation of ALT was increased significantly, however, AST, TC and TG were no significant difference in the ALC group.
2 Compared with the normal control group, the ALT, AST, TG and TC were all increased significantly, the level of TG and TC in liver homogenate and liver index were increased significantly, hepatic steatosis and inflammatory infiltration were observed by pathological examination in the HFLM group.
3 With different dose of CH, hepatic steatosis was improved in dose-response and dose-dependent manner. Compared with the normal control group, the liver index, serum TG, TC, ALT and AST levels, and hepatic TG, TC, MDA level markedly increased (all P<0.01); and hepatic SOD and GSH-Px significantly decreased (both P<0.0l) in the model control group. Compared with the model control group, serum TG, TC, ALT and AST, and hepatic TG, TC, MDA markedly decreased(P<0.01 or P<0.05); and hepatic SOD and GSH-Px significantly increased(both P<0.01) in the high-dose Cepharanthine Hydrochloride treatment group.
Conclusion:
Mice HFLM were successfully established by injecting DEX plus high fat diet. The HFLD has metabolic disturbance of blood fat and hepatic injury simultaneously which is worth further comprehensive evaluation. CH has good therapeutic action on hyperlipidemic fatty liver disease. The possible mechanism is that CH can improve antioxidase activity and depress lipid peroxidation of fatty liver.
高脂性脂肪肝是非酒精性脂肪肝的一种类型,它从单纯性脂肪变性可能发展为脂肪性肝炎、肝纤维化甚至肝硬化。高脂性脂肪肝的高发病率越来越引起人们的重视。积极研发其治疗的理想药物意义重大。本课题探讨建立小鼠高脂性脂肪肝动物模型的方法,并观察盐酸千金藤碱(CH)对该模型的治疗作用,尤其是对该模型小鼠脂代谢和脂质过氧化机制方面的影响。
材料与方法：
(1)分别观察三种脂肪肝动物模型：四氯化碳、地塞米松加高脂饮食、酒精所致小鼠脂肪肝模型血脂的变化,检测小鼠血脂水平和转氨酶活性,以筛选表现高脂血症的动物模型。
(2)通过腹腔注射地塞米松的同时灌服高脂乳剂复制小鼠高脂性脂肪肝模型,检测小鼠血脂及肝脂水平,同时进行肝脏组织病理学检查,进一步确定小鼠高脂性脂肪肝模型的建立。
(3)复制地塞米松和高脂饮食所致的小鼠高脂性脂肪肝模型,应用不同剂量CH对其进行治疗,并以注射用硫普罗宁为阳性对照药,检测小鼠血脂及肝脂水平、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性、丙二醛(MDA)含量等指标,同时进行肝脏病理组织切片观察小鼠肝脏细胞改善情况。
结果：
(1)与正常对‘照组相比,四氯化碳模型组血清中丙氨酸转氨酶(ALT)天冬氨酸转氨酶(AST)活性显著升高(P<0.01),血脂甘油三酯(TG)及总胆固醇(TC)没有统计学差异；地塞米松模型组血清中两种转氨酶活性和血脂都显著性升高(P<0.01)；酒精模型组血清ALT活性显著升高(P<0.01),其他三项指标无显著性差异。
(2)与正常对照组相比,小鼠脂肪肝模型组血清中TG、TC、ALT、AST均显著性升高(P<0.01),肝匀浆中TG、TC含量及肝脏指数亦显著性增高(P<0.01),病理检查可见肝组织脂肪变性及炎性浸润,表明成功建立小鼠高脂性脂肪肝模型。
(3)与对照组相比,模型组小鼠血清TG、TC、ALT、AST活性和肝组织TG、TC、MDA含量显著升高(P<0.01),肝组织SOD和GSH-Px活性显著降低(P<0.01),以及肝脏病理组织学检查均表明成功建立了小鼠高脂性脂肪肝模型。CH高剂量组小鼠血清TG、TC、ALT、AST及肝组织TG、TC、MDA显著低于模型组(P<0.01或P<0.05),肝组织SOD和GSH-Px活性显著高于模型组(P<0.01)；通过大体标本和肝脏病理学检查得知,不同剂量CH均能改善肝细胞脂肪变性情况,以高剂量组最为明显。
结论：
(1)三种模型中,地塞米松加高脂饮食所致脂肪肝小鼠模型中同时存在血脂代谢紊乱及肝脏损伤,值得进一步全面评价。
(2)成功建立地塞米松和高脂饮食所致的小鼠高脂性脂肪肝模型。
(3)CH对地塞米松和高脂饮食所致的小鼠高脂性脂肪肝具有良好的治疗作用,其机制可能与其能够提高抗氧化酶活性、抑制脂质过氧化反应等方面有关。
Background&Purpose:
Hyperlipidemic fatty liver disease (HFLD) is one kind of non-alcoholic fatty liver disease. The simple steatosis may develop to steatohepatitis, liver fibrosis or cirrhosis. It is caused more attention by the high incidence. It is of great significance to develop the ideal drug to treat HFLD. To study and establish the animal model of hyperlipidemic fatty liver in mice and to observe the therapeutic effects of Cepharanthine Hydrochloride (CH) against the models induced by Dexamethasone (DEX) and high-fat diet in mice.
Materials and methods:
1 Three fatty liver animal models were produced by carbon tetrachloride (CTC), DEX and alcohol (ALC). The total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), aspartate amintransferase (AST) in the serum were measured.
2 Hyperlipidemic fatty liver model (HFLM) was produced by injecting Dexamethasone Sodium Phosphate injection in the mice'abdomen and feeding mice high-fat diet at one time. The TC, TG, ALT, AST in the serum and the TC, TG in the liver were measured. Liver tissues were observed with optical microscope.
3 The hyperlipidemic fatty liver mice models were prevented with different doses (low, middle and high) contrasting with Tiopronin. The TC, TG, ALT, AST in the serum and the TC, TG, superoxide dismutase (SOD), maeic dialdehyde (MDA), glutathion peroxidase (GSH-Px) in the liver were measured. Liver tissues were observed.
Results:
1 Compared with the normal control group, the activations of ALT and AST were increased significantly (p<0.01), TG and TC were no significant difference in the CTC group; The TC, TG, ALT and AST in the serum were increased significantly in DEX group (p<0.01); the activation of ALT was increased significantly, however, AST, TC and TG were no significant difference in the ALC group.
2 Compared with the normal control group, the ALT, AST, TG and TC were all increased significantly, the level of TG and TC in liver homogenate and liver index were increased significantly, hepatic steatosis and inflammatory infiltration were observed by pathological examination in the HFLM group.
3 With different dose of CH, hepatic steatosis was improved in dose-response and dose-dependent manner. Compared with the normal control group, the liver index, serum TG, TC, ALT and AST levels, and hepatic TG, TC, MDA level markedly increased (all P<0.01); and hepatic SOD and GSH-Px significantly decreased (both P<0.0l) in the model control group. Compared with the model control group, serum TG, TC, ALT and AST, and hepatic TG, TC, MDA markedly decreased(P<0.01 or P<0.05); and hepatic SOD and GSH-Px significantly increased(both P<0.01) in the high-dose Cepharanthine Hydrochloride treatment group.
Conclusion:
Mice HFLM were successfully established by injecting DEX plus high fat diet. The HFLD has metabolic disturbance of blood fat and hepatic injury simultaneously which is worth further comprehensive evaluation. CH has good therapeutic action on hyperlipidemic fatty liver disease. The possible mechanism is that CH can improve antioxidase activity and depress lipid peroxidation of fatty liver.
引文
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