Identification of novel peroxisome proliferator-activated receptor α (PRARα) target genes in mouse liver using cDNA microarray analysis
Identification of novel peroxisome proliferator-activated receptor α (PRARα) target genes in mouse liver using cDNA microarray analysis
复制标题
DOI：
10.3727/000000001783992533
复制
发表时间：
2001-01-01
期刊：
影响因子：
--
通讯作者：
Reddy, JK
中科院分区：
文献类型：
--
作者：
Cherkaoui-Malki, M;Meyer, CM;Reddy, JK
过氧化物酶体增殖剂作为过氧化物酶体增殖物激活受体α (PPAR α)激动剂，是一组结构多样的非遗传毒性肝癌致癌物，包括贝特类降血脂药物，可诱导肝实质细胞中过氧化物酶体增殖。这些药物持续激活PPAR α导致大鼠和小鼠肝脏肿瘤的发展。为了了解这些药物的多效性作用的分子机制，我们利用cDNA微阵列生成了小鼠肝脏中基因表达的分子图谱，这些小鼠使用了强效过氧化物酶体增殖剂wy - 14643治疗2周。PPAR α激活导致36个基因的表达增加（4倍以上），671个基因的表达减少（4倍以上）。一些参与脂质和糖代谢的基因以及许多其他与过氧化物酶体生物发生、细胞表面功能、转录、细胞周期和凋亡相关的基因的表达增强。这些包括：CYP2B9， CYP2B10，单甘油酯脂肪酶，丙酮酸脱氢酶-激酶-4，细胞死亡诱导dna断裂因子- α，过氧化物酶体生物发生因子11 β，以及一些细胞识别表面蛋白，包括膜联蛋白A2， CD24, CD39，淋巴细胞抗原6和视黄酸早期转录- γ等。从PPAR α(-/-)小鼠和缺乏PPAR α和过氧化物酶体脂肪酰基辅酶a氧化酶（AOX）的小鼠肝脏中提取的总RNA进行Northern印迹检测，这些小鼠分别被喂食对照组和含有wey -14,1643的饮食2周，以及单剂量wey -14,643诱导后的时间过程，显示通过微阵列技术鉴定的基因上调依赖于过氧化物酶体相对于PPAR α的增殖。诱导细胞死亡的dna片段化因子- α mRNA在野生型小鼠肝脏中增加，而在自发过氧化物酶体增殖的AOX（-/-）小鼠中没有增加。这些观察结果表明，PPAR α的激活导致许多与过氧化物酶体无关的基因表达的增加和减少，并且一些基因表达增强的延迟发作可能是PPAR α激活和脂质代谢改变继发的代谢事件的结果。
Peroxisome proliferators, which function as peroxisome proliferator-activated receptor-alpha (PPAR alpha) agonists, are a group of structurally diverse nongenotoxic hepatocarcinogens including the fibrate class of hypolipidemic drugs that induce peroxisome proliferation in liver parenchymal cells. Sustained activation of PPAR alpha by these agents leads to the development of liver tumors in rats and mice. To understand the molecular mechanisms responsible for the pleiotropic effects of these agents, we have utilized the cDNA microarray to generate a molecular portrait of gene expression in the liver of mice treated for 2 weeks with Wy-14,643, a potent peroxisome proliferator. PPAR alpha activation resulted in the stimulation of expression (fourfold or greater) of 36 genes and decreased the expression (fourfold or more decrease) of 671 genes. Enhanced expression of several genes involved in lipid and glucose metabolism and many other genes associated with peroxisome biogenesis, cell surface function, transcription, cell cycle, and apoptosis has been observed. These include: CYP2B9, CYP2B10, monoglyceride lipase, pyruvate dehydrogenase-kinase-4, cell death-inducing DNA-fragmentation factor-alpha, peroxisomal biogenesis factor 11 beta, as well as several cell recognition surface proteins including annexin A2, CD24, CD39, lymphocyte antigen 6, and retinoic acid early transcript-gamma, among others. Northern blotting of total RNA extracted from the livers of PPAR alpha (-/-) mice and from mice lacking both PPAR alpha and peroxisomal fatty acyl-CoA oxidase (AOX), that were fed control and Wy-14,1643-containing diets for 2 weeks, as well as time course of induction following a single dose of Wy-14,643, revealed that upregulation of genes identified by microarray procedure is dependent upon peroxisome proliferation vis-a-vis PPAR alpha However, cell death-inducing DNA-fragmentation factor-alpha mRNA, which is increased in the livers of wild-type mice treated with peroxisome proliferators, was not enhanced in AOX(-/-) mice with spontaneous peroxisome proliferation. These observations indicate that the activation of PPAR alpha leads to increased and decreased expression of many genes not associated with peroxisomes, and that delayed onset of enhanced expression of some genes may be the result of metabolic events occurring secondary to PPAR alpha activation and alterations in lipid metabolism.