Peroxisome proliferator activated receptor-α expression in human liver
Peroxisome proliferator activated receptor-α expression in human liver
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DOI：
10.1124/mol.53.1.14
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发表时间：
1998-01-01
影响因子：
3.6
通讯作者：
Johnson, EF
中科院分区：
文献类型：
--
作者：
Palmer, CNA;Hsu, MH;Johnson, EF
过氧化物酶体增殖物激活受体α (PPAR)是类固醇/激素受体超家族的成员，介导编码几种过氧化物酶体和微粒体酶的过氧化物酶体增殖物依赖基因的转录激活以及过氧化物酶体增殖。人类肝脏对小鼠过氧化物酶体增殖物的病理作用是不耐受的。使用RNase保护实验，发现人类肝脏PPAR α mRNA与β -肌动蛋白mRNA的比例比小鼠低1个数量级。此外，由于交替RNA剪接导致PPAR α缺乏外显子6，因此无法编码功能性PPAR的人类PPAR α cDNA的分离表明，这一过程也可能减少PPAR α的表达。总RNA的RNase保护分析显示，在所检查的所有10个人类肝脏样本中，剪接变体缺失外显子6的水平显著。利用CYP4A6-Z过氧化物酶体增殖反应元件和PPAR α特异性抗血清进行的超移分析显示，小鼠肝脏裂解液中PPAR α DNA结合活性的含量很容易检测到，而人肝脏裂解液中PPAR α DNA结合活性的含量比小鼠裂解液低10倍。与小鼠裂解液相比，人肝脏裂解液中PPAR α的结合量通常低于其他未知蛋白。这些结果表明，尽管人类保留了功能性受体的编码潜力，但肝脏中PPAR α的低水平表达可能不足以与与过氧化物酶体增殖反应元件结合的其他蛋白质有效竞争。
The peroxisome proliferator activated receptor alpha (PPAR) is a member of the steroid/hormone receptor superfamily that mediates the peroxisome proliferator-dependent transcriptional activation of genes encoding several peroxisomal and microsomal enzymes as well as peroxisome proliferation. Human liver is refractory to the pathological effects of peroxisome proliferators that are seen in mice. With the use of RNase protection assays, the ratio of hepatic PPAR alpha mRNA to beta-actin mRNA was found to be 1 order of magnitude lower in humans than that observed in mice. In addition, the isolation of human cDNA for PPAR alpha that does not encode a functional PPAR because it lacks exon 6 as a result of alternate RNA splicing suggested that this process might also diminish the expression of PPAR alpha. RNase protection analysis of total RNA revealed the presence of splice variants lacking exon 6 at significant levels in all 10 human liver samples examined. Supershift analysis using the CYP4A6-Z peroxisome proliferator response element and antisera specific for PPAR alpha revealed easily detectable amounts of PPAR alpha DNA binding activity in mouse liver lysates, whereas human liver lysates contained >10-fold lower amounts of PPAR alpha DNA binding activity, In contrast to mouse lysates, the amount of PPAR alpha binding in human lysates was generally less than that of other unidentified proteins. These results suggest that although humans retain the coding potential for a functional receptor, the low levels of PPAR alpha expression in liver may be insufficient to compete effectively with other proteins that bind to peroxisome proliferator response elements.