Lehmann J M, Lenhard J M, Oliver B B, Ringold G M, Kliewer S A
Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
J Biol Chem. 1997 Feb 7;272(6):3406-10. doi: 10.1074/jbc.272.6.3406.
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 (PPARgamma), a ligand-activated transcription factor known to play a pivotal role in adipogenesis. The concentration of indomethacin required to activate PPARgamma 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 PPARgamma ligands and induce adipocyte differentiation of C3H10T1/2 cells. Finally, we show that the same NSAIDs that activate PPARgamma are also efficacious activators of PPARalpha, 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 PPARgamma ligands and provide a molecular basis for the biological effects of these drugs on adipogenesis and peroxisome activity.
吲哚美辛是一种非甾体抗炎药（NSAID）和环氧化酶抑制剂，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处理各种前脂肪细胞系可促进其终末分化。然而，吲哚美辛促脂肪生成作用的分子基础仍不清楚。在本报告中，我们表明吲哚美辛结合并激活过氧化物酶体增殖物激活受体γ（PPARγ），一种已知在脂肪生成中起关键作用的配体激活转录因子。激活PPARγ所需的吲哚美辛浓度与诱导C3H10T1/2细胞分化为脂肪细胞所需的浓度高度一致。我们证明其他几种NSAIDs，包括非诺洛芬、布洛芬和氟芬那酸，也是PPARγ配体，并能诱导C3H10T1/2细胞向脂肪细胞分化。最后，我们表明激活PPARγ的相同NSAIDs也是PPARα的有效激活剂，PPARα是一种在肝脏中富集的PPAR亚型，在过氧化物酶体增殖中起关键作用。有趣的是，已有报道称几种NSAIDs在体外和体内均可诱导肝细胞中的过氧化物酶体活性。我们的研究结果定义了一组新的PPARγ配体，并为这些药物对脂肪生成和过氧化物酶体活性的生物学效应提供了分子基础。
