Ovine 11beta-hydroxysteroid dehydrogenase: from gene to function

Abstract

Two distinct isoforms of 11β-hydroxysteroid dehydrogenase (11β-HSD) with respect to enzymatic activity were identified in the ovine liver and kidney. 11β-HSD1 (the hepatic isoform) was reversible and NADP(H)-dependent. By contrast, 11β-HSD2 (the renal isoform) was unidirectional and NAD-dependent. Ovine placenta contained both forms of 11β-HSD activities. The cDNA encoding ovine 11β-HSD1 was cloned, and used as a probe to study 11β-HSD1 gene expression in fetal sheep during development. It was found that fetal and adult liver was the major site of 11β-HSD1 biosynthesis, and that 11β-HSD1 gene expression was regulated in a tissue-specific and developmentally programmed manner. Two non-functional variants of 11β-HSD1 were also identified. In addition, sheep kidney was unique in that both 11β-HSD1 mRNA and activity were absent. Although the physiological significance of 11β-HSD in individual fetal organs during development remains largely speculative, 11β-HSD in the fetal pituitary may contribute, at least in part, to the proposed resetting of cortisol negative feedback on pituitary ACTH during the last few days of gestation. In the fetal liver, the action of 11β-HSD may lead to the formation of cortisol which could act locally as well as systematically to modulate developmental processes. Placental 11β-HSD may protect fetus from exposure to the growth-inhibiting effects of maternal glucocorticoids.