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目的探讨大黄酸联合吡格列酮对高脂诱建的大鼠NASH协同治疗及其可能的作用机制。方法清洁级SD大鼠140~160 g,♂,76只正常喂养1周后,随机分成6组(对照组、模型组各为14只,余组均为12只):对照组,模型组,大黄酸组,吡格列酮组,大黄酸吡格列酮联合低剂量组,高剂量组。模型组高脂高胆固醇饲料由普通饲料+10%猪油+2%胆固醇配制,药物组均在12周高脂饮食后即造模成功后给予干预。大黄酸用生理盐水配成5 g.L 1混悬液,每天固定时间100 mg.kg 1.d 1灌胃,吡格列酮组8 mg.kg 1.d 1,联合低剂量组取其相对有效低剂量,大黄酸50 mg.kg 1.d 1,吡格列酮组4 mg.kg 1.d 1。联合高剂量组为大黄酸100 mg.kg 1.d 1,吡格列酮组8 mg.kg 1.d 1。于第20周处死。所有动物测体重、肝湿重,计算肝指数;测空腹血糖、转氨酶及血脂水平,放免法测空腹胰岛素及TNF-,计算胰岛素抵抗指数;酶法测定肝组织匀浆MDA、GSH-PX水平;HE染色肝病理组织切片。结果第20周模型组大鼠血糖、胰岛素、血脂、ALT、AST及胰岛素抵抗指数较对照组明显增高;肝组织出现重度脂肪变性,均出现小叶内炎症细胞浸润和散在的灶性坏死;药物组大鼠的生化指标和脂肪变及炎症程度较模型组均有明显减轻,联合组较药物单用组更为有效。结论大黄酸联合吡格列酮较两药单用能更有效抑制脂质过氧化反应及改善胰岛素抵抗,对大鼠NASH具有明显的协同治疗作用。
Objective To investigate the synergistic effect of rhein combined with pioglitazone on rat NASH induced by high fat and its possible mechanism. Methods One hundred (140-160) g SD rats were randomly divided into 6 groups (control group, 14 in each model group and 12 in control group): control group, model group, Rhein group, pioglitazone group, pioglitazone combined with low-dose group, high-dose group. The model group of high-fat and high-cholesterol diet was formulated with normal diet + 10% lard + 2% cholesterol. The drug group was given intervention after successful 12-week high-fat diet. Rhein with physiological saline dubbed 5 gL 1 suspension daily fixed time 100 mg.kg 1.d 1 intragastric administration, pioglitazone group 8 mg.kg 1.d 1, combined with low-dose group to take its relatively effective low-dose, Rhein acid 50 mg.kg 1.d 1, pioglitazone group 4 mg.kg 1.d 1. Combination of high-dose group rhein 100 mg.kg 1.d 1, pioglitazone group 8 mg.kg 1.d 1. On the 20th week of execution. All animals were weighed, the wet weight of liver was measured and the liver index was calculated. The fasting blood glucose, transaminase and lipids were measured, the fasting insulin and TNF-α were measured by radioimmunoassay, and the indexes of insulin resistance were calculated. The levels of MDA and GSH- HE staining of liver biopsy. Results At the 20th week, the blood glucose, insulin, blood lipid, ALT, AST and insulin resistance index in the model group were significantly higher than those in the control group. The severe fatty degeneration in the liver tissue occurred in the lobular tissue and infiltration of inflammatory cells in the lobular tissue. Compared with the model group, the biochemical indexes, steatosis and inflammation of the rats were significantly reduced. The combined group was more effective than the single drug group. Conclusion Rhein combined with pioglitazone can inhibit lipid peroxidation and improve insulin resistance more effectively than either alone or in combination with two drugs. It has obvious synergistic therapeutic effect on rat NASH.