Ohnesorg Thomas, Keller Brigitte, Hrabé de Angelis Martin, Adamski Jerzy
School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, Adelaide University, Adelaide 5005, South Australia, Australia.
J Mol Endocrinol. 2006 Aug;37(1):185-97. doi: 10.1677/jme.1.02043.
In both humans and mice, 17beta-hydroxysteroid dehydrogenase type-7 (HSD17B7) was described as possessing dual enzymatic functionality. The enzyme was first shown to be able to convert estrone to estradiol in vitro. Later involvement of this enzyme in postsqualene cholesterol biosynthesis was postulated (conversion of zymosterone to zymosterol) and could be proven in vitro. In this work, we performed a detailed analysis of the transcriptional regulation of both the human and murine genes. Despite relatively low sequence similarity, both promoters contain similar contexts of transcription factor-binding sites. The participation of these sites in transcriptional regulation of HSD17B7 was proven by electro-mobility shift assay and site-directed mutagenesis of the corresponding binding sites. We describe novel involvement of vitamin D receptor/retinoid X receptor and provide new information on the regulation of HSD17B7 expression by sterol regulatory element-binding protein and hepatocyte nuclear factor 4, the latter known from other genes of cholesterogenic enzymes. The results of our study provide unequivocal evidence for a role of HSD17B7 in cholesterol biosynthesis.
在人类和小鼠中，17β-羟类固醇脱氢酶7型（HSD17B7）被描述为具有双重酶功能。该酶首先在体外被证明能够将雌酮转化为雌二醇。后来推测该酶参与了鲨烯后胆固醇的生物合成（将酵母甾酮转化为酵母甾醇），并且这一点在体外得到了证实。在这项工作中，我们对人类和小鼠基因的转录调控进行了详细分析。尽管序列相似性相对较低，但两个启动子都含有相似的转录因子结合位点背景。通过电泳迁移率变动分析和相应结合位点的定点诱变，证明了这些位点参与了HSD17B7的转录调控。我们描述了维生素D受体/视黄酸X受体的新作用，并提供了关于固醇调节元件结合蛋白和肝细胞核因子4对HSD17B7表达调控的新信息，后者在其他胆固醇生成酶基因中也有发现。我们的研究结果为HSD17B7在胆固醇生物合成中的作用提供了明确的证据。
