高脂饮食致脂肪肝胰岛素抵抗大鼠模型中PPARs的表达及作用

The expression and effect of peroxisome proliferators activate receptors in rat fatty liver models with insulin resistance caused by high fat diet

目的研究PPARα、PPARγ在SD大鼠NAFLD/NASH的形成中的作用,并初步从胰岛素抵抗(IR)方面探讨其机制。方法将SD大鼠60只随机分为正常对照组(NC组,n=20)、高脂对照组(FC组,n=20),高脂加罗格列酮组(FR组,n=10)、高脂加非诺贝特组(FF组,n=10)。饲养12周末时随机取NC组与FC组各10只一并做高胰岛素正葡萄糖钳夹实验及肝组织的HE染色,确定造模成功。然后给予罗格列酮、非诺贝特及继续高脂饮食干预,共4周。氨基转移酶、三酰甘油等以生物化学方法测定,并以逆转录-聚合酶链反应(RT-PCR)技术分析PPARα、PPARγ基因的mRNA表达水平。结果 FC组大鼠呈高脂血症,与NC组比较,PPARα的mRNA表达下调,而PPARγmRNA表达上调(P<0.05),IR和肝细胞脂肪变及炎性程度加重(P<0.05);与FC组比较,FF及FR组PPARα的mRNA表达上调,PPARγmRNA表达下调,IR明显改善(P<0.05)。结论在高脂饮食诱导的NASH、IR模型中,PPARα、PPARγ的mRNA表达水平与IR密切相关,可以共同促进NASH的进展,而使用PPARs激动剂后对大鼠NASH及IR起到了有效治疗作用。

Objective To investigate the effect of peroxisome proliferators activate receptors （ PPARα, PPARγ） on formation of NAFLD/NASH in SD rats and to explore initially the mechanisms of insulin resistance （IR）. Methods 60 male SD rats were randomly divided into four groups ： normal control group （ NC group, n = 20）, high fat control group （ HFC group, n = 20）, high fat ＋ rosiglitazone group （ HFR group, n = 10）, high fat ＋ fenofibrate group （HFF group, n = 10）. After 12-week feeding, 10 rats in NC group and 10 rats in HFC group were randomly selected to be tested by glucose clamp test and liver tissue HE staining in order to identify whether the models were successful. Then the rats were given rosiglitazone, fenofibrate and continuous high fat diet intervention for 4 weeks. At last the levels of aminotransferase, triglyceride were measured by biochemistry, and the mRNA expression levels of PPARot and PPARγgenes were detected by the reverse transcriptase-polymerase chain reaction （RT-PCR）. Results Hyperlipidemia was found in FC group. As compared with those in HFC group the expression levels of PPARαmRNA in NC group were down-regulated, however, the expression levels of PPARγ mRNA were up regulated （ P 〈 0.05）. Furthermore, the IR, steatosis and inflammatory degree were aggravated in HFC group （ P 〈0.05）. As compared with those in HFC group,the expression levels of PPARαmRNA in HFF group and HFR group were up regulated, however, the expression levels PPARγmRNA were down regulated, and IR was obviously improved. Conclusion The expression levels of PPARα mRNA and PPARγ mRNA are closely correlated to IR in NASH and IR models induced by high fat diet,which may promote the progress of NASH,while the administration of PPARs agonist has effective therapeutic effect on NASH and IR in rats.