Regulation of P450 4A expression by peroxisome proliferator activated receptors
Regulation of P450 4A expression by peroxisome proliferator activated receptors
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DOI：
10.1016/s0300-483x(02)00282-2
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发表时间：
2002-12-27
期刊：
影响因子：
4.5
通讯作者：
Griffin, KJ
中科院分区：
文献类型：
--
作者：
Johnson, EF;Hsu, MH;Griffin, KJ
过氧化体增殖物(PPS)和脂肪酸对P450 4A酶的诱导作用是由PPARpha介导的，PPARpha作为异源二聚体与维甲酸X受体(RXR)结合到靶基因的反应元件上。PPAR/RXR异源二聚体识别的共同序列包含由单个核苷酸隔开的两个核受体结合基序的不完全直接重复。该重复序列之前是一个保守的A/T丰富序列，这是功能所必需的。在小鼠中，长期暴露于PPS会导致PPARa介导的肝脏肥大、增生和癌变，并伴随着过氧化物体的增殖。相反，人类对PP发病的敏感性降低。这可能反映了>；PPARpha水平比小鼠低10倍，以及靶向基因的差异。为了识别对PPAR有反应的人类基因，对人肝癌细胞系HepG2进行了基因改造，使其表达水平增加的PPARα。在这些细胞中，编码酮体形成的限速酶和分支点的几个基因受到PPARa的调控。相比之下，PP对与小鼠中的过氧酶体增殖相关的过氧化体脂肪酸氧化的显著诱导作用并不明显。人P450 4A11在PPARα水平升高的细胞分裂培养中不表达，但在融合培养中表达PPARa水平升高。(C)2002爱思唯尔科学爱尔兰有限公司。保留所有权利。
The induction of P450 4A enzymes by peroxisome proliferators (PPs) and fatty acids is mediated by the peroxisome proliferator activated receptor alpha (PPARalpha) that binds to response elements in target genes as a heterodimer with the retinoid X receptor (RXR). The consensus sequence recognized by PPAR/RXR heterodimers, contains an imperfect direct repeat of two nuclear receptor binding motifs separated by a single nucleotide. This repeat is preceded by a conserved A/T rich sequence that is required for function. In mice, chronic exposure to PPs results in PPARa mediated liver hypertrophy, hyperplasia and carcinogenesis accompanied by a proliferation of peroxisomes. In contrast, humans exhibit a reduced sensitivity to PP pathogenesis. This could reflect > 10-fold lower PPARalpha levels relative to mice as well as differences in targeted genes. In order to identify PPAR responsive human genes, the human hepatoma cell line, HepG2, was engineered to express increased levels of PPARalpha. Several genes encoding rate-limiting enzymes and branch points in ketone body formation are regulated by PPARa in these cells. In contrast, significant induction by PP is not evident for peroxisomal fatty acid oxidation that is associated with peroxisome proliferation in mice. Human P450 4A11 is not expressed in dividing cultures of cells with enhanced PPARalpha levels, but it is expressed in confluent cultures expressing elevated amounts of PPARa. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.