The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification
The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification
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DOI：
10.1016/j.cmet.2006.04.015
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发表时间：
2006-07-01
期刊：
影响因子：
29
通讯作者：
Schibler, Ueli
中科院分区：
文献类型：
--
作者：
Gachon, Federic;Olela, Fabienne Fleury;Schibler, Ueli
PAR结构域碱性亮氨酸拉链（PAR bZip）转录因子DBF、TEF和HLF以高度昼夜节律的方式在几种外周组织（包括肝脏和肾脏）中积累。缺乏这三种蛋白质的小鼠出生时具有预期的孟德尔比率，但容易癫痫，衰老速度加快，并过早死亡。在识别PAR bZip靶基因的表达改变可能有助于高发病率和死亡率的PAR bZip三重敲除小鼠的希望，我们比较了这些动物的肝脏和肾脏转录组的野生型或杂合突变小鼠。这些实验表明，PAR bZip蛋白控制许多酶和调节剂参与解毒和药物代谢，如细胞色素P450酶，羧酸酯酶，和组成型雄烷受体（CAR）的表达。事实上，PAR bZip三重敲除小鼠对异生物质化合物过敏，解毒的缺乏可能导致其早期衰老。
The PAR-domain basic leucine zipper (PAR bZip) transcription factors DBF, TEF, and HLF accumulate in a highly circadian manner in several peripheral tissues, including liver and kidney. Mice devoid of all three of these proteins are born at expected Mendelian ratios, but are epilepsy prone, age at an accelerated rate, and die prematurely. In the hope of identifying PAR bZip target genes whose altered expression might contribute to the high morbidity and mortality of PAR bZip triple knockout mice, we compared the liver and kidney transcriptomes of these animals to those of wild-type or heterozygous mutant mice. These experiments revealed that PAR bZip proteins control the expression of many enzymes and regulators involved in detoxification and drug metabolism, such as cytochrome P450 enzymes, carboxylesterases, and constitutive androstane receptor (CAR). Indeed, PAR bZip triple knockout mice are hypersensitive to xenobiotic compounds, and the deficiency in detoxification may contribute to their early aging.