Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs
Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs
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DOI：
10.1074/jbc.272.6.3406
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发表时间：
1997-02-07
影响因子：
4.8
通讯作者：
Kliewer, SA
中科院分区：
文献类型：
--
作者：
Lehmann, JM;Lenhard, JM;Kliewer, SA
吲哚美辛是一种非甾体抗炎药（NSAID）和环加氧酶抑制剂，经常被用作研究脂肪细胞分化过程的研究工具。在胰岛素存在的情况下，用微摩尔浓度的吲哚美辛治疗各种前脂肪细胞系可促进其终末分化。然而，吲哚美辛增脂作用的分子基础尚不清楚。在本报告中，我们发现吲哚美辛结合并激活过氧化物酶体增殖体激活受体γ (PPAR γ)，这是一种已知在脂肪形成中起关键作用的配体激活转录因子。激活PPAR γ所需的吲哚美辛浓度与诱导C3H10T1/2细胞向脂肪细胞分化所需的浓度一致。我们证明了其他几种非甾体抗炎药，包括非诺洛芬、布洛芬和氟芬酸，也是PPAR γ配体，并诱导C3H10T1/2细胞的脂肪细胞分化。最后，我们发现激活PPAR γ的非甾体抗炎药也是PPAR α的有效激活剂，PPAR α是一种肝脏富集的PPAR亚型，在过氧化物酶体增殖中起关键作用。有趣的是，一些非甾体抗炎药已被报道在体外和体内诱导肝细胞的过氧化物酶体活性。我们的发现定义了一组新的PPAR γ配体，并为这些药物对脂肪形成和过氧化物酶体活性的生物学效应提供了分子基础。
Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) and cyclooxygenase inhibitor that is frequently used as a research tool to study the process of adipocyte differentiation. Treatment of various preadipocyte cell lines with micromolar concentrations of indomethacin in the presence of insulin promotes their terminal differentiation. However, the molecular basis for the adipogenic actions of indomethacin had remained unclear. In this report, we show that indomethacin binds and activates peroxisome proliferator-activated receptor gamma (PPAR gamma), a ligand-activated transcription factor known to play a pivotal role in adipogenesis. The concentration of indomethacin required to activate PPAR gamma is in good agreement with that required to induce the differentiation of C3H10T1/2 cells to adipocytes. We demonstrate that several other NSAIDs, including fenoprofen, ibuprofen, and flufenamic acid, are also PPAR gamma ligands and induce adipocyte differentiation of C3H10T1/2 cells. Finally, we show that the same NSAIDs that activate PPAR gamma are also efficacious activators of PPAR alpha, a liver-enriched PPAR subtype that plays a key role in peroxisome proliferation. Interestingly, several NSAIDs have been reported to induce peroxisomal activity in hepatocytes both in vitro and in vivo. Our findings define a novel group of PPAR gamma ligands and provide a molecular basis for the biological effects of these drugs on adipogenesis and peroxisome activity.