Individual differences of the regulation mechanism of the human carboxylesterase gene

哺乳动物羧酸酯酶（CES）包含一个多基因家族，其基因产物定位于内质网。我们最近描述了人类肝脏中 CES 的主要形式，称为 CES HU1，属于 CES1 家族，并且它被认为在药物和脂质代谢中发挥着重要作用。由于CES HU1的表达水平可能影响药物和脂质的水平，因此了解CES HU1基因表达的调节机制非常重要。在本研究中，我们分离出了编码人类CES HU1的两个CES基因，暂定为CES HU1a和CES HU1b。两个基因都以反向重复形式存在于 16 号染色体上。除了外显子 1 和推定的顺式元件外，这些基因完全相似。 CES HU1a 在人肝脏中的转录水平远高于 CES HU1b。缺失分析和电泳迁移率变动分析的结果表明从-160到54的区域由两个基因启动子组成。然而，Sp1和C/EBP与CES HU1 a启动子相互作用，但不与CES HUM启动子相互作用。结论是，这两个基因很可能源自早期基因复制事件，并且它们高度保守的结构和转录水平调控的差异有力地证明了每种基因产物在细胞代谢中的重要作用。

Mammalian carboxylesterase (CES) comprise a multigene family, which gene products are localized in the endoplasmic reticulum. We have recently described that major forms of CES in the human liver termed CES HU1 belongs to the CES1 family and that it is thought to play an important roles in drug and lipid metabolism. Since the expression level of CES HU1 may affect the level of drugs and lipid, it is important to understand the mechanism by which CES HU1 gene expression is regulated. In this study, we isolated the two CES genes encoding human CES HU1, which were tentatively designated as CES HU1a and CES HU1b. Both genes exist in inverted duplication on chromosome 16. These genes were completely similar, except for exon 1 and putative cis elements. The transcriptional level of CES HU1a was much higher than CES HU1b in human livers. Results of deletion assays and electrophoretic mobility shift assays suggested that the region from -160 to +54 consisted of the both gene promoters. However, Sp1 and C/EBP interacted with the CES HU1 a promoter, but not CES HUM promoter. It was concluded that these two genes most probably arose from an early gene duplication event and that their highly conserved structures and difference in regulation at the transcriptional level argue strongly for a significant role for each gene product in cellular metabolism.