Hanselman J C, Vartanian M A, Koester B P, Gray S A, Essenburg A D, Rea T J, Bisgaier C L, Pape M E
Department of Molecular Biology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert, Ann Arbor, MI, USA.
Mol Cell Biochem. 2001 Jan;217(1-2):91-7. doi: 10.1023/a:1007248007372.
Two alternatively spliced forms of human PPAR alpha mRNA, PPAR alpha1 and PPAR alpha2, have been identified. PPAR alpha1 mRNA gives rise to an active PPAR alpha protein while PPAR alpha2 mRNA gives rise to a form of PPAR which lacks the ligand-binding domain. PPAR alpha2 is unable to activate a peroxisome proliferator response element (PPRE) reporter gene construct in transient transfection assays. Both PPAR alpha1 and PPAR alpha2 mRNA are present in human liver, kidney, testes, heart, small intestine, and smooth muscle. In human liver, PPAR alpha2 mRNA abundance is approximately half that of PPAR alpha1 mRNA; a correlation analysis of PPAR alpha1 and PPAR alpha2 mRNA mass revealed an r-value of 0.75 (n = 18). Additional studies with intact liver from various species, showed that the PPAR alpha2/PPAR alpha1 mRNA ratios in rat, rabbit, and mouse liver were less than 0.10; significantly lower than the 0.3 and 0.5 ratios observed in monkey and human livers, respectively. To determine if a high PPAR alpha2/PPAR alpha1 mRNA ratio was associated with insensitivity to peroxisome proliferators, we treated human, rat, and rabbit hepatocytes with WY14643, a potent PPAR alpha activator, and measured acyl CoA oxidase (ACO) mRNA levels. Rat ACO mRNA levels increased markedly in response to WY14643 while human and rabbit hepatocytes were unresponsive. Thus, although the PPAR alpha2/PPAR alpha1 mRNA ratio is low in rabbits, this species is not responsive to peroxisome proliferators. Further studies with male and female rats, which vary significantly in their response to peroxisome proliferators, showed little difference in the ratio of PPAR alpha2/PPAR alpha1 mRNA. These data suggest that selective PPAR alpha2 mRNA expression is not the basis for differential species or gender responses to peroxisome proliferators.
已鉴定出人类PPARα mRNA的两种可变剪接形式，即PPARα1和PPARα2。PPARα1 mRNA产生一种活性PPARα蛋白，而PPARα2 mRNA产生一种缺乏配体结合结构域的PPAR形式。在瞬时转染实验中，PPARα2无法激活过氧化物酶体增殖物反应元件（PPRE）报告基因构建体。PPARα1和PPARα2 mRNA均存在于人类肝脏、肾脏、睾丸、心脏、小肠和平滑肌中。在人类肝脏中，PPARα2 mRNA丰度约为PPARα1 mRNA的一半；对PPARα1和PPARα2 mRNA量的相关性分析显示r值为0.75（n = 18）。对来自各种物种的完整肝脏进行的进一步研究表明，大鼠、兔子和小鼠肝脏中PPARα2/PPARα1 mRNA比率小于0.10；分别显著低于在猴子和人类肝脏中观察到的0.3和0.5的比率。为了确定高PPARα2/PPARα1 mRNA比率是否与对过氧化物酶体增殖剂不敏感有关，我们用强效PPARα激活剂WY14643处理人类、大鼠和兔子的肝细胞，并测量酰基辅酶A氧化酶（ACO）mRNA水平。大鼠ACO mRNA水平对WY14643有明显升高反应，而人类和兔子肝细胞无反应。因此，尽管兔子中PPARα2/PPARα1 mRNA比率较低，但该物种对过氧化物酶体增殖剂无反应。对过氧化物酶体增殖剂反应差异显著的雄性和雌性大鼠进行的进一步研究表明，PPARα2/PPARα1 mRNA比率几乎没有差异。这些数据表明，选择性PPARα2 mRNA表达不是物种或性别对过氧化物酶体增殖剂反应差异的基础。
