Peroxisome proliferator-activated receptors, coactivators, and downstream targets
Peroxisome proliferator-activated receptors, coactivators, and downstream targets
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DOI：
10.1385/cbb:32:1-3:187
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发表时间：
2000-03-01
影响因子：
2.6
通讯作者：
Reddy, JK
中科院分区：
文献类型：
--
作者：
Qi, C;Zhu, YJ;Reddy, JK
肝实质细胞中的过氧化物酶体对结构多样的非致突变化合物（称为过氧化物酶体增殖物（PP））作出反应而增殖。在大鼠和小鼠中，过氧化物酶体增殖和过氧化物酶体脂肪酸β-氧化系统的持续诱导导致肝肿瘤的发展。两个机制问题是重要的考虑：阐明上游事件负责fur组织和物种特异性诱导的特征多效性反应的PP;以及描绘与过氧化物酶体增殖相关的下游事件，以及它们在对过氧化物酶体增殖的诱导敏感的物种中的肝肿瘤的发展中的作用。过氧化物酶体增殖的诱导是由PP-介导的。活化受体α（PPAR α），一组调节与脂质代谢和脂肪细胞分化相关的基因表达的转录因子的成员。该核受体家族的三种同种型，即PPARalpha、PPARgamma和PPARdelta（也称为beta），已被鉴定为不同基因的产物。虽然PPARalpha负责PP诱导的多效性反应，但PPARgamma似乎参与脂肪形成和分化，但与PPARgamma相关的事件不直接涉及过氧化物酶体和过氧化物酶体增殖。PPARs与9-顺式视黄酸受体（RXR）异源二聚化，并与靶基因启动子上的PP反应元件（PPREs）结合以启动诱导型转录活性。组织和物种对PPs的反应取决于药代动力学、PPAR同种型的相对丰度、靶基因上游区域PPRE的性质、核转录因子对PPAR异源二聚化伴侣类维生素A X受体的竞争或串扰程度以及辅激活因子和辅抑制因子对PPARs配体依赖性转录的调节作用。以过氧化物酶体增殖物激活受体（PPAR）为诱饵，在酵母双杂交系统中克隆了小鼠类固醇受体辅激活因子1（SRC-1）和过氧化物酶体增殖物激活受体结合蛋白（PBP），并鉴定为PPAR辅激活因子。SRC-1和PBP都含有LXXLL签名基序，被认为是辅激活因子与核受体结合所必需和足够的。一个多方面的方法，其中包括额外的辅激活因子，可能是负责毛皮细胞特异性转录激活的PPAR介导的靶基因，并产生转基因动物（转基因和基因破坏）的鉴定，将有必要获得更多的洞察上游和下游目标负责诱导早期和延迟Pr诱导的多效性反应。在这种情况下，重要的是要注意，小鼠缺乏脂肪酰辅酶A氧化酶，过氧化物酶体β-氧化系统的第一个和限速酶，揭示了这种酶是必不可少的生理调节的过氧化物酶体α，这种酶的缺乏导致持续的转录激活的基因调节该受体。
Peroxisomes in liver parenchymal cells proliferate in response to structurally diverse nonmutagenic compounds designated as peroxisome proliferators (PP). Sustained induction of peroxisome proliferation and peroxisomal fatty acid beta-oxidation system in rats and mice leads to the development of liver tumors. Two mechanistic issues are important for consideration: elucidation of the upstream events responsible fur the tissue and species specific induction of the characteristic pleiotropic responses by PPs; and delineation of the downstream events associated with peroxisome proliferation, and their role in the development of liver tumors in species that are sensitive to the induction of peroxisome proliferation The induction of peroxisome proliferation is mediated by PP-activated receptor alpha (PPAR alpha), a member of a group of transcription factors that regulate the expression of genes associated with lipid metabolism and adipocyte differentiation. Three isotypes of this family of nuclear receptors, namely PPAR alpha, PPAR gamma, and PPAR delta (also called beta), have been identified as products of separate genes. Although PPAR alpha is responsible for the PP-induced pleiotropic responses, PPAR gamma seems to be involved in adipogenesis and differentiation, but the events associated with PPAR gamma do not directly involve peroxisomes and peroxisome proliferation. PPARs heterodimerize with 9-cis retinoic acid receptor (RXR), and bind to PP response element(s) (PPREs) on the target gene promoter to initiate inducible transcriptional activity. Tissue and species responses to PPs depend on pharmacokinetics, relative abundance of PPAR isotypes, nature of PPRE in the upstream regions of target genes, the extent of competition or cross-talk among nuclear transcription factors for PPAR heterodimerization partner retinoid X receptor and the modulating role of coactivators and corepressors on ligand-dependent transcription of PPARs. Using PPAR as bait in the yeast two-hybrid system, the authors recently cloned mouse steroid receptor coactivator-1 (SRC-1) and PPAR-binding protein (PBP), and identified them as PPAR coactivators. Both SRC-1 and PBP contain LXXLL signature motifs, considered necessary and sufficient for the binding of coactivators to nuclear receptors. A multifaceted approach, which includes the identification of additional coactivators that may be responsible fur cell specific transcriptional activation of PPAR-mediated target genes, and generation of genetically modified animals (transgenic and gene disrupted), will be necessary to gain more insight into the upstream and downstream targets responsible for the induction of early and delayed Pr-induced pleiotropic responses. Ln this context, it is important to note that mice deficient in fatty acyl-CoA oxidase, the first and rate-limiting enzyme of the peroxisomal beta-oxidation system, revealed that this enzyme is indispensable for the physiological regulation of PPAR alpha, and the absence of this enzyme leads to sustained transcriptional activation of genes regulated by this receptor.