Activation of PPARδ alters lipid metabolism in db/db mice
Activation of PPARδ alters lipid metabolism in db/db mice
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DOI：
10.1016/s0014-5793(00)01554-4
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发表时间：
2000-05-19
期刊：
影响因子：
3.5
通讯作者：
Auwerx, J
中科院分区：
文献类型：
--
作者：
Leibowitz, MD;Fiévet, C;Auwerx, J
过氧化物酶体增殖物激活受体（PPARs）是一种核受体，它与类维生素A X受体异源二聚化，并与受调控基因启动子中的过氧化物酶体增殖物反应元件结合。尽管关于PPAR α和PPAR γ的功能有丰富的信息，但对于表达最广泛的PPAR亚型--PPAR δ--却知之甚少。在这里，我们表明，治疗胰岛素抵抗db/db小鼠与PPAR δ激动剂L-165041，在剂量没有任何影响，无论是葡萄糖或甘油三酯，提高总血浆胆固醇浓度。快速蛋白液相色谱分析显示，胆固醇升高主要与高密度脂蛋白（HDL）颗粒有关。这些数据通过超离心分离的脂蛋白的化学分析得到证实，表明用L-165041处理产生循环HDL的增加，而极低或低密度脂蛋白没有重大变化。白色脂肪组织脂蛋白脂酶活性在用PPAR δ配体处理后降低，但在用PPAR γ激动剂处理后升高。这些数据表明，PPARdelta参与db/db小鼠胆固醇代谢的调节，PPARdelta配体可能具有潜在的治疗价值。(C)2000年欧洲生物化学学会联合会。
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which heterodimerize with the retinoid X receptor and bind to peroxisome proliferator response elements in the promoters of regulated genes. Despite the wealth of information available on the function of PPAR alpha and PPAR gamma, relatively little is known about the most widely expressed PPAR subtype, PPAR delta. Here we show that treatment of insulin resistant db/db mice with the PPAR delta agonist L-165041, at doses that had no effect on either glucose or triglycerides, raised total plasma cholesterol concentrations. The increased cholesterol was primarily associated,vith high density lipoprotein (HDL) particles, as shown by fast protein liquid chromatography analysis. These data,were corroborated by the chemical analysis of the lipoproteins isolated by ultracentrifugation, demonstrating that treatment with L-165041 produced an increase in circulating HDL without major changes in very low or low density lipoproteins. White adipose tissue lipoprotein lipase activity,vas reduced following treatment with the PPAR delta ligand, but was increased by a PPAR gamma agonist. These data suggest both that PPAR delta is involved in the regulation of cholesterol metabolism in db/db mice and that PPAR delta ligands could potentially have therapeutic value. (C) 2000 Federation of European Biochemical Societies.