Peroxisome proliferator-activated receptors: Structures and function
Peroxisome proliferator-activated receptors: Structures and function
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DOI：
10.1111/j.1749-6632.1996.tb18620.x
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发表时间：
1996-01-01
期刊：
影响因子：
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通讯作者：
Woodyatt, NJ
中科院分区：
文献类型：
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作者：
Tugwood, JD;Aldridge, TC;Woodyatt, NJ
我们一直试图阐明过氧化物酶体增殖剂发挥其多效性作用的分子机制，特别强调理解为什么人类似乎对这些化合物无反应。有大量的数据表明过氧化物酶体增殖物激活受体α（过氧化物酶体增殖物激活受体α）介导啮齿类动物的这些作用; PPARalpha在对PPs有生理反应的组织中表达，在体外被多种PPs转录激活，最近证实缺乏该受体的小鼠对氯贝特和Wy-14，643的作用不敏感，至少在短期内是如此。可以想象，有反应的啮齿动物和无反应的人类受试者之间的PPAR α差异可能提供了理解这种物种反应差异基础的关键，考虑到这一点，我们一直在研究人类的PPAR α生物学，并研究个体间的差异。已经有发表的证据，虽然只有两个序列，结构和功能的多态性，在人类过氧化物酶体增殖物激活受体α。我们已经扩展了这些发现，并表明：有相当大的变化，从不同的个人获得的hPPAR α cDNA，在总的结构水平（缺乏编码外显子）和更微妙的性质（单碱基变化导致氨基酸取代）。一个这样的cDNA，其序列与公开的序列仅在三个氨基酸上不同，编码一种不能被有效PP转录激活的受体。hPPARalpha转录本在人类肝脏中表达的程度在个体之间可以变化高达一个数量级。人类中的组织特异性表达谱与大鼠和小鼠中的组织特异性表达谱非常不同。特别是，人类肝脏中的PPAR α水平通常较低，而啮齿类动物的反应性较强，其中有效的PPs会导致肝脏肿瘤。两者合计，这些数据表明，首先，人类和啮齿动物的过氧化物酶体增殖物激活受体α不同，根据一些分子和生化标准，其次，有一定程度的个体间的变化，在过氧化物酶体增殖物激活受体α的结构和功能。研究正在进行中，以进一步澄清这一点，但人类的多态性可能会在某种程度上解释明显的矛盾，即活性PPAR α受体可以从一个“无反应”的物种中分离出来。
We have been attempting to elucidate the molecular mechanisms through which peroxisome proliferators exert their pleiotropic effects, with particular emphasis on understanding why humans appear unresponsive to these compounds. There is a wealth of data to implicate the peroxisome proliferator-activated receptor alpha (PPAR alpha) in mediating these effects in rodent species; PPAR alpha is expressed in tissues that show physiological changes in response to PPs, is transcriptionally activated in vitro by a variety of PPs, and it has been recently demonstrated that mice lacking this receptor are refractory to the effects of clofibrate and Wy-14,643, at least in the short term. It is conceivable that differences in PPAR alpha between responsive rodent and unresponsive human subjects may provide the key to understanding the basis of this species variation in response, and with this in mind we have been studying the biology of PPAR alpha in humans and looking at interindividual variation. There is already published evidence, albeit on only two sequences, for structural and functional polymorphism in human PPAR alphas. We have extended these findings, and shown that: There is considerable variation in hPPAR alpha cDNAs obtained from different individuals, both at the gross structural level (lack of a coding exon) and of a more subtle nature (single base changes leading to amino acid substitutions). One such cDNA, the sequence of which differs at only three amino acids from that published, encodes a receptor that is incapable of transcriptional activation by potent PPs. The degree to which hPPAR alpha transcripts are expressed in human livers can vary by up to an order of magnitude between individuals. The tissue-specific expression profile of PPAR alpha in humans is very different from that in rat and mouse. In particular, the human liver contains generally low levels of PPAR alpha in contrast to the responsive rodents, in which potent PPs cause liver tumors. Taken together, these data suggest first that human and rodent PPAR alphas differ according to a number of molecular and biochemical criteria, and secondly that there is a degree of interindividual variation in PPAR alpha structure and function. Studies are ongoing to clarify this further, but human polymorphism may go some way towards explaining the apparent paradox that active PPAR alpha receptors can be isolated from an" unresponsive" species.