过氧化物增殖激活受体α激动剂非诺贝特下调大鼠肝脏糖皮质激素受体表达

目的 探讨过氧化物增殖激活受体α(PPAR-α)激动剂非诺贝特对大鼠糖皮质激素受体(GR)表达调节作用.方法 30 只雄性SD大鼠随机分为对照组,FE1组(非诺贝特50mg·kg~(-1)·d~(-1),1个月),FE2组(非诺贝特100 mg·kg~(-1)·d~(-1),1个月),FE3组(非诺贝特100mg·kg~(-1)·d~(-1),2个月),MK886组同时给予非诺贝特(100 mg·kg~(-1)·d~(-1))和PPARa抑制剂MK886(30 mg·kg~(-1)·d~(-1)),1个月].检测SD大鼠肝脏、肌肉、脂肪组织GR基因和蛋白表达水平,同时测定肾上腺11β-羟化酶(CYP11B1)基因表达水平,并以放免法测定大鼠血皮质酮水平.结果 非诺贝特显著下调了大鼠肝脏组织GR基因和蛋门质表达水平,FE1、FE2和FE3 3组GR mRNA水平分别较正常组降低55%、54%、68%,蛋白质表达水平分别降低了28%、77%和99%;并升高.肾上腺CYP11B1表达水平及血中皮质酮水平,而MK886完全逆转了非诺贝特的这些效应正常组、FE1、FE2、FE3、MK886组皮质酮水平分别为(393±23)、(495±44)、(516±18)、(622±93)、(382±37)ng/ml],提示非诺贝特可抑制肝脏GR表达,并促进肾上腺皮质酮合成增多,这些作用依赖于PPARα激活.结论 PPARα激活剂非诺贝特可抑制肝脏GR表达.

Agonist-induced down-regulation of hepatic glucocorticoid receptor via peroxisome proliferator-activated receptor in SD rats

Objective It was reported that a negative feedback loop might exist between pemxisome proliferator-activated receptor alpha (PPARa) and glucocorticoid receptor (GR).However,it is unclear whether GR expression is regulated by PPARct activation.To further demonstrate this possibility,we conducted the present study to investigate the regulatory effects of the PPARα agonist fenofibrate on GR expression in Sprague-Dawley rats.Methods GR gene and protein expression levels were determined in liver,visceral and muscle tissues.Adrenal 11 β-hydroxylase (CYP11B1) expression was examined by RT-PCR and circulating corticosterone level was measured by RIA method.Results GR expression was reduced by fenofibrate in a time-and does-dependent manner.The GR mRNA in the three fenofibrate groups of rats were 55%(FE1),54%(FE2) and 68% (FE3) lower than that of the control rats.The GR protein were 28%.77% and 99% lower than the control.The inhibition was observed in liver,but not in fat and muscle.The coaicosterone level in the blood was increased significantly by fenofibrate (the levels of corticorsterone in control.FE1,FE2,FE3,MK886 groups were (393±23)、(495±44)、(516±18)、(622±93)、(382±37) ng/ml respectively.These effects of fenofibrate were abolished by PPARα inhibitor MK886.suggesting that fenoffbrate activated throush PPARα.Conclusion A new molecular mechanism has been found for a negative feedback regulation of GR activity by PPARα in SD rats.