神效托里散对CCl4诱导的大鼠肝纤维化作用及代谢组学研究

Metabolomics Study and Effect of Shenxiao Tuolisan on CCl4-induced Hepatic Fibrosis Rats

关键词:  神效托里散  肝纤维化  代谢组学  作用机制

Key words:  Shenxiao Tuolisan  hepatic fibrosis  metabolomics  mechanism

摘要:

目的 探讨神效托里散对CCl₄所致大鼠肝纤维化的作用及其可能的作用机制。方法 采用40% CCl₄(2 mL·kg^–1)诱导大鼠肝纤维化模型，每周2次，共计8周。造模第6周开始灌胃给予神效托里散，给药时间为8周。采用脏器指数及Masson染色评价抗肝纤维化的药效；采用HPLC-QTOF-MS联用技术检测神效托里散干预后各组大鼠血浆中代谢物的变化，利用Ropls软件进行偏最小二乘法判别分析、差异代谢物筛选及代谢通路分析。结果 脏器指数结果显示，神效托里散可以不同程度地降低大鼠的肝指数、脾指数，升高胸腺指数，与模型组比较差异具有统计学意义(P<0.01)；Masson染色结果表明，神效托里散干预后肝脏中纤维结缔组织增生变浅变窄，与空白组大鼠较接近；代谢组学分析显示，与模型组比较，神效托里散干预后共有385种代谢物发生变化，其中上调的有20种，下调的有365种，如花生四烯酸、皮质酮、胆汁酸、亚油酸等。主要与脂解的调节、亚油酸代谢、胆汁分泌、鞘脂信号通路、不饱和脂肪酸的生物合成等代谢途径有关。结论 神效托里散对CCl₄所致大鼠肝纤维化具有很好的防治作用，其作用机制可能与脂解的调节、胆汁酸代谢、脂肪酸代谢等途径有关。

Abstract:

OBJECTIVE To explore the effect of Shenxiao Tuolisan on CCl₄-induced hepatic fibrosis in rats and its possible mechanism. METHODS The rat hepatic fibrosis model was established by intragastric administration of 40% CCl₄(2 mL·kg^–1),twice a week for 8 weeks.After the intervention of Shenxiao Tuolisan at 6 week for 8 weeks.Evaluated anti-fibrotic efficacy by organ index and Masson staining.HPLC-QTOF-MS combined technology was used to detect the changes of metabolites in the plasma of rats in each group.Ropls software was used to partial least squares discriminant analysis,differential metabolite screening and metabolic pathway analysis.RESULTS The organ index results showed that Shenxiao Tuolisan could reduce the liver index and spleen index,increase the thymus index in different degrees,and there was a significant difference compared with the model group (P<0.01).The results of Masson staining showed that the hyperplasia of fibrous connective tissue in the liver became shallower and narrower after the intervention of Shenxiao Tuolisan.Metabolomics analysis indicated that,compared to the model control group,385 metabolites changed after the intervention of Shenxiao Tuolisan,of which 20 were up-regulated and 365 were down-regulated,such as arachidonate acid,cholic acid,linoleate acid.Mainly related to regulation of lipolysis in adipocytes,linoleic acid metabolism,bile secretion,sphingolipid signaling pathway,biosynthesis of unsaturated fatty acids.CONCLUSION Shenxiao Tuolisan has a good effect on CCl₄-induced hepatic fibrosis in rats,and its mechanism of action may be related to the regulation of lipolysis in adipocytes,bile acid synthesis and other metabolic pathways.