A peroxisome proliferator-activated receptor-alpha (PPARα) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARα:: implications for species differences in responses to peroxisome proliferators
A peroxisome proliferator-activated receptor-alpha (PPARα) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARα:: implications for species differences in responses to peroxisome proliferators
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DOI：
10.1007/s002040050483
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发表时间：
1998-02-01
影响因子：
6.1
通讯作者：
Roberts, RA
中科院分区：
文献类型：
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作者：
Tugwood, JD;Holden, PR;Roberts, RA
过氧化物酶体增殖剂类非遗传毒性啮齿类肝癌物质在给予大鼠和小鼠时会导致肝细胞 DNA 合成、过氧化物酶体增殖和肝脏肿瘤，但不能诱导其他物种（包括豚鼠、狗和包括人类在内的灵长类动物）的肝细胞 S 期或过氧化物酶体增殖。有令人信服的数据表明，核受体过氧化物酶体增殖物激活受体-α (PPAR α) 是过氧化物酶体增殖物 (PP) 毒性和致癌作用的重要介质。我们有兴趣将豚鼠视为人类对这些化合物反应的可能模型。该手稿描述了从豚鼠肝脏中分离编码 PPAR α 的全长 cDNA，该基因与先前在小鼠、大鼠和人类中发现的受体密切相关。 RNA杂交实验表明，PP反应性大鼠和小鼠的肝脏中含有相对较高水平的PPARα转录物，而在人和豚鼠肝脏中，PPARαmRNA的含量要低得多。功能分析表明豚鼠 PPAR α 能够被 PP 激活。使用体外翻译蛋白进行的 DNA 结合研究表明，在存在类视黄醇 X 受体 (RXR) 的情况下，豚鼠受体能够与 DNA 特异性结合，瞬时转染测定表明，豚鼠 PPAR α 能够被 PP Wy-14,643 和 nafenopin 以浓度依赖性方式转录激活。此外，在豚鼠原代肝细胞培养物中，PPAR α 的显性负性阻遏物消除了 PP 对自发性细胞凋亡的抑制。总而言之，这些数据表明“无反应”豚鼠肝脏中活性 PPAR α 的表达水平降低，并且可能是探索人类对 PP 反应的机制的有用模型。
The peroxisome proliferator class of non-genotoxic rodent hepatocarcinogens cause hepatocyte DNA synthesis, peroxisome proliferation and liver tumours when administered to rats and mice, but fail to induce S-phase or peroxisome proliferation in hepatocytes from other species including guinea-pigs, dogs, and primates including humans. There are compelling data that implicate a nuclear receptor, the peroxisome proliferator-activated receptor-alpha (PPAR alpha) as an important mediator of the toxic and carcinogenic effects of peroxisome proliferators (PPs). We were interested to consider the guinea-pig as a possible model for human responses to these compounds. This manuscript describes the isolation of a full-length cDNA encoding PPAR alpha from guinea-pig liver that is closely related to receptors identified previously in mouse, rat and human. RNA hybridisation experiments suggested that the livers of the PP-responsive rat and mouse contained relatively high levels of PPAR alpha transcripts, whereas in human and guinea-pig liver PPAR alpha mRNA was much less abundant. Functional analyses suggested that the guinea-pig PPAR alpha was able to be activated by PPs. DNA binding studies using in vitro translated proteins showed that the guinea-pig receptor was able to bind specifically to DNA in the presence of the retinoid X receptor (RXR), and transient transfection assays showed that the guinea-pig PPAR alpha was capable of being transcriptionally activated in a concentration-dependent fashion by the PPs Wy-14,643 and nafenopin. Also, in guinea-pig primary hepatocyte cultures, a dominant negative repressor of PPAR alpha ablated the suppression of spontaneous apoptosis by PPs. Taken together, these data show that the 'non-responsive' guinea-pig expresses active PPAR alpha in the liver at reduced levels, and may be a useful model for exploring the mechanisms underlying the human response to PPs.