Bird A Daniel, Greatorex Spencer, Reser David, Lavery Gareth G, Cole Timothy J
Department of Biochemistry and Molecular BiologyMonash University, Melbourne, Victoria, Australia.
Department of PhysiologyMonash University, Melbourne, Victoria, Australia.
Endocr Connect. 2017 Oct;6(7):489-499. doi: 10.1530/EC-17-0119.
Steroid hormones play clinically important and specific regulatory roles in the development, growth, metabolism, reproduction and brain function in human. The type 1 and 2 11-beta hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 2) have key roles in the pre-receptor modification of glucocorticoids allowing aldosterone regulation of blood pressure, control of systemic fluid and electrolyte homeostasis and modulation of integrated metabolism and brain function. Although the activity and function of 11β-HSDs is thought to be understood, there exists an open reading frame for a distinct 11βHSD-like gene; , which is present in human, non-human primate, sheep, pig and many other higher organisms, whereas an orthologue is absent in the genomes of mouse, rat and rabbit. We have now characterised this novel gene as encoded by 9 exons and analysis of EST library transcripts indicated the use of two alternate ATG start sites in exons 2 and 3, and alternate splicing in exon 9. Relatively strong gene expression was detected in human, non-human primate and sheep tissue samples from the brain, ovary and testis. Analysis in non-human primates and sheep by immunohistochemistry localised HSD11B1L protein to the cytoplasm of ovarian granulosa cells, testis Leydig cells, and gonadatroph cells in the anterior pituitary. Intracellular localisation analysis in transfected human HEK293 cells showed HSD1L protein within the endoplasmic reticulum and sequence analysis suggests that similar to 11βHSD1 it is membrane bound. The endogenous substrate of this third HSD enzyme remains elusive with localisation and expression data suggesting a reproductive hormone as a likely substrate.
类固醇激素在人类的发育、生长、代谢、生殖和脑功能中发挥着临床上重要且特定的调节作用。1型和2型11-β羟类固醇脱氢酶（11β-HSD1和2）在糖皮质激素的受体前修饰中起关键作用，从而使醛固酮能够调节血压、控制全身液体和电解质平衡以及调节整体代谢和脑功能。尽管人们认为已了解11β-HSDs的活性和功能，但存在一个独特的类11βHSD基因的开放阅读框；该基因存在于人类、非人类灵长类动物、绵羊、猪和许多其他高等生物中，而在小鼠、大鼠和兔子的基因组中不存在直系同源物。我们现已将这个新基因鉴定为由9个外显子编码，对EST文库转录本的分析表明在第2和第3外显子中使用了两个交替的ATG起始位点，并且在第9外显子中存在交替剪接。在人类、非人类灵长类动物和绵羊的脑、卵巢和睾丸组织样本中检测到相对较强的基因表达。通过免疫组织化学在非人类灵长类动物和绵羊中进行的分析将HSD11B1L蛋白定位到卵巢颗粒细胞、睾丸间质细胞和垂体前叶促性腺细胞的细胞质中。在转染的人HEK293细胞中进行的细胞内定位分析显示HSD1L蛋白在内质网中，序列分析表明它与11βHSD1类似，是膜结合的。这种第三种HSD酶的内源性底物仍然难以捉摸，定位和表达数据表明一种生殖激素可能是底物。
