PDF(Pubmed)
Abstract：
Three peroxisome proliferator-activated receptor subtypes, PPARα, PPAR(ß/)δ, and PPARγ, exert ligand-dependent transcriptional control in concert with retinoid X receptors (RXRs) on various gene sets harboring PPAR response elements (PPREs) in their promoter regions. Ligand-bound PPAR/RXR complexes do not directly regulate transcription; instead, they recruit multiprotein coactivator complexes to specific genomic regulatory loci to cooperatively activate gene transcription. Several coactivators are expressed in a single cell; however, a ligand-bound PPAR can be associated with only one coactivator through a consensus LXXLL motif. Therefore, altered gene transcription induced by PPAR subtypes/agonists may be attributed to the recruitment of various coactivator species. Using a time-resolved fluorescence resonance energy transfer assay, we analyzed the recruitment of four coactivator peptides (PGC1α, CBP, SRC1, and TRAP220) to human PPARα/δ/γ-ligand-binding domains (LBDs) using eight PPAR dual/pan agonists (bezafibrate, fenofibric acid, pemafibrate, pioglitazone, elafibranor, lanifibranor, saroglitazar, and seladelpar) that are/were anticipated to treat nonalcoholic fatty liver disease. These agonists all recruited four coactivators to PPARα/γ-LBD with varying potencies and efficacy. Only five agonists (bezafibrate, pemafibrate, elafibranor, lanifibranor, and seladelpar) recruited all four coactivators to PPARδ-LBD, and their concentration-dependent responses differed from those of PPARα/γ-LBD. These results indicate that altered gene expression through consensus PPREs by different PPAR subtypes/agonists may be caused, in part, by different coactivators, which may be responsible for the unique pharmacological properties of these PPAR agonists.
摘要：
三种过氧化物酶体增殖物激活受体亚型，PPARα,PPAR(β/)δ，和PPARγ，与类视黄醇X受体（RXR）协同作用，在其启动子区域具有PPAR响应元件（PPREs）的各种基因集上发挥配体依赖性转录控制。配体结合的PPAR/RXR复合物不直接调节转录；相反，他们招募多蛋白共激活复合物到特定的基因组调控位点以协同激活基因转录。几种共激活剂在单个细胞中表达；然而，配体结合的PPAR只能通过共有LXXLL基序与一种共激活剂结合。因此,PPAR亚型/激动剂诱导的基因转录改变可能归因于各种共激活因子物种的募集。使用时间分辨荧光共振能量转移测定法，我们分析了四种共激活肽(PGC1α，CBP,SRC1和TRAP220）使用八种PPAR双重/泛激动剂（苯扎贝特，非诺贝酸,匹马贝特,吡格列酮,Elafibranor,羊膜，saroglitazar,和seladelpar）预期用于治疗非酒精性脂肪性肝病。这些激动剂均以不同的效力和功效招募了PPARα/γ-LBD的四种共激活剂。只有五种激动剂(苯扎贝特，匹马贝特,Elafibranor,羊膜，和seladelpar)招募了所有四种共激活剂到PPARδ-LBD，它们的浓度依赖性反应与PPARα/γ-LBD不同。这些结果表明，不同的PPAR亚型/激动剂通过共有PPREs引起的基因表达改变，在某种程度上,通过不同的助活化剂，这可能是这些PPAR激动剂独特的药理学性质的原因。
