Institut für Molekularbiologie und Tumorforschung, Philipps-Universität Marburg, 35032 Marburg, Germany.
Mol Pharmacol. 2010 Feb;77(2):171-84. doi: 10.1124/mol.109.060541. Epub 2009 Nov 10.
Peroxisome proliferator-activated receptor (PPARs) modulate target gene expression in response to unsaturated fatty acid ligands, such as arachidonic acid (AA). Here, we report that the AA metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) activates the ligand-dependent activation domain (AF2) of PPARbeta/delta in vivo, competes with synthetic agonists in a PPARbeta/delta ligand binding assay in vitro, and triggers the interaction of PPARbeta/delta with coactivator peptides. These agonistic effects were also seen with PPARalpha and PPARgamma, but to a significantly weaker extent. We further show that 15-HETE strongly induces the expression of the bona fide PPAR target gene Angptl4 in a PPARbeta/delta-dependent manner and, conversely, that inhibition of 15-HETE synthesis reduces PPARbeta/delta transcriptional activity. Consistent with its function as an agonistic ligand, 15-HETE triggers profound changes in chromatin-associated PPARbeta/delta complexes in vivo, including the recruitment of the coactivator cAMP response element-binding protein binding protein. Both 15R-HETE and 15S-HETE are similarly potent at inducing PPARbeta/delta coactivator binding and transcriptional activation, indicating that 15-HETE enantiomers generated by different pathways function as PPARbeta/delta agonists.
过氧化物酶体增殖物激活受体 (PPARs) 可调节靶基因的表达，以响应不饱和脂肪酸配体，如花生四烯酸 (AA)。在这里，我们报告说 AA 的代谢物 15-羟基二十碳四烯酸 (15-HETE) 在体内激活 PPARβ/delta 的配体依赖性激活结构域 (AF2)，在体外与合成激动剂竞争 PPARβ/delta 配体结合测定，并触发 PPARβ/delta 与共激活肽的相互作用。这些激动作用也见于 PPARα 和 PPARγ，但程度明显较弱。我们进一步表明，15-HETE 以 PPARβ/delta 依赖性方式强烈诱导真正的 PPAR 靶基因 Angptl4 的表达，相反，抑制 15-HETE 的合成会降低 PPARβ/delta 的转录活性。与其作为激动剂配体的功能一致，15-HETE 在体内引发与染色质相关的 PPARβ/delta 复合物的深刻变化，包括共激活因子 cAMP 反应元件结合蛋白结合蛋白的募集。15R-HETE 和 15S-HETE 在诱导 PPARβ/delta 共激活剂结合和转录激活方面同样有效，表明由不同途径产生的 15-HETE 对映体作为 PPARβ/delta 激动剂发挥作用。
