肝气郁结型代谢综合征与肝X受体的实验研究

Metabolic syndrome is a variety of cardiovascular risk factors in the build-up within the individual state, its etiology and pathogenesis is not yet fully elucidated, in medicine there is no specific treatment of multi-target drugs. According to the research understanding of the ancient physicians and modern Chinese medicine symptom,stagnation of the liver-Qi is a basis and important symptom in the early traditional chinese medical symptoms, by basic theories of the differentiation of syndromes,preliminary studies have shown that Chinese medicine treating stagnation of the liver-Qi type of metabolic syndrome has a good clinical efficacy. The liver X receptor is the multi-targetly intervented research focus,and it is involved in a variety of physiological activities,including the metabolism and transportation of cholesterol,the formation of fat and gluconeogenes, wherefore these have a strong correlation with Chinese medicine multi-target therapy and the overall regulation of Chinese medicine in theory. We will establish the early and mid-and late metabolic syndrome animal model which is similar to human metabolic syndrome, and detect the mRNA of liver x receptor of a and β expressed level to clarify the role of liver X receptors in metabolic syndrome.And then stagnation of the liver-Qi type metabolic syndrome animal models will be feed up, by using the method of soothing the liver and regulating qi to treat animal models of stagnation of the liver-Qi type metabolic syndrome,detecting the liver x receptor of a and β mRNA expressed level as the starting point to evaluate the efficacy of the method of soothing the liver and regulating qi,we hope that the project will provide a new targeted basis for early intervention to metabolic syndrome with Chinese medicine.

代谢综合征是心血管多种危险因素在个体内集结的状态，其病因和发病机制尚不确切，目前医学在治疗上也无特异性的多靶点药物。根据古代医家及现代中医证候研究认识，肝气郁是MS早期重要的中医基础证候，前期研究表明中医治疗肝郁型代谢综合征有很好的临床疗效。目前肝X受体是多靶点干预研究热点，其参与包括胆固醇的代谢和转运、脂肪的形成、糖原异生在内的机体多种生理活动的调节，与中医的整体调节，中药的多靶点治疗在理论上有很强的关联性。本项目希望通过建立与人类代谢综合征相似的MS前期及中后期动物模型，检测肝x受体a和β的mRNA表达水平，阐明肝x受体在MS前期的作用，并建立肝郁型代谢综合征动物模型，再以疏肝理气法治疗肝郁型代谢综合征动物模型，评价其疗效，以检测肝x受体a和β的mRNA表达为切入点，探讨中医疏肝理气法疗效的作用机制、物质基础、靶点及可能的途径，为中医临床早期干预MS疗效评价及预后评估提供新的靶向依据。

肝气郁是代谢综合征（MS）早期重要的中医基础证候，肝X受体是多靶点干预研究热点，其参与包括胆固醇的代谢和转运、脂肪的形成、糖原异生在内的机体多种生理活动的调节，与中医的整体调节，中药的多靶点治疗在理论上有很强的关联性。本项目主要通过构建肝郁型MS大鼠，探讨LXRmRNA的动态表达变化及柴胡疏肝散对肝郁型MS大鼠LXRmRNA的影响。方法：采用高脂饲料喂养配合情志刺激束缚法诱导自发性高血压大鼠（SHR）建立肝郁型MS大鼠模型，检测大鼠TC、TG、LDL-C、HDL-C、FBG、FIN、HOMA-IR指数，开野实验评分，RT-PCR检测大鼠肝肝脏LXRα和βmRNA表达。将肝郁型MS大鼠随机分为高脂药物干预组（FI）、高脂对照组（FC），将对照组大鼠随机分为普食干预组（NI）以及普食对照组（NC），干预组给予柴胡疏肝散灌胃，对照组给予生理盐水灌胃。在干预前后检测各组生化指标以及肝脏LXRα和βmRNA表达。结果：开野实验方面，肝郁型MS组大鼠与对照组比较，水平以及垂直运动两部分开野试验得分较NC组明显下降；血脂方面，与对照组比较，肝郁型MS组TC、TG以及LDL-C均有差异；血糖方面，与对照组比较，肝郁型MS组FBG、FIN、HOMA-IR均升高；血压方面，与对照组比较，肝郁型MS组SBP均有差异；LXRmRNA表达方面，第8周，与对照组比较，肝郁型MS组LXRαmRNA表达升高；第16周，与对照组比较，肝郁型MS组LXRαmRNA下降；药物干预后，FI组与FC组比较，TC、LDL-C、HOMA-IR差异有统计学意义；FI组与FC组比较，LXRαmRNA表达有差异统计学意义。结论：本研究应用高脂饲养配合束缚情志刺激法能够成功构建肝郁型MS大鼠模型；研究提示在代谢综合征代偿期早期LXRα表达升高可能一种改善胰岛素抵抗的代偿调节机制；柴胡舒肝散具有改善肝郁型MS大鼠血糖、血脂代谢，其作用机制可能与通过调节LXRαmRNA表达改善胰岛素抵抗有关。