Drareg
Member
- Joined
- Feb 18, 2016
- Messages
- 4,772
"11β-Hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2 catalyze the interconversion of inactive and active glucocorticoids. Impaired regulation of these enzymes has been associated with obesity, diabetes, hypertension, and cardiovascular disease. Previous studies in animals and humans suggested that dehydroepiandrosterone (DHEA) has antiglucocorticoid effects, but the underlying mechanisms are unknown. In this study, DHEA treatment markedly increased mRNA expression and activity of 11β-HSD2 in a rat cortical collecting duct cell line and in kidneys of C57BL/6J mice and Sprague-Dawley rats. DHEA-treated rats tended to have reduced urinary corticosterone to 11-dehydrocorticosterone ratios. It was found that CCAAT/enhancer-binding protein-α (C/EBP-α) and C/EBP-β regulated HSD11B2transcription and that DHEA likely modulated the transcription of 11β-HSD2 in a phosphatidylinositol-3 kinase/Akt-dependent manner by increasing C/EBP-β mRNA and protein expression. Moreover, it is shown that C/EBP-α and C/EBP-β differentially regulate the expression of 11β-HSD1 and 11β-HSD2. In conclusion, DHEA induces a shift from 11β-HSD1 to 11β-HSD2 expression, increasing conversion from active to inactive glucocorticoids. This provides a possible explanation for the antiglucocorticoid effects of DHEA.
Enhanced glucocorticoid effects, mainly as a result of locally disturbed glucocorticoid metabolism, contribute to diseases such as hypertension and the metabolic syndrome.1–3 The adrenal steroid hormone precursor dehydroepiandrosterone (DHEA) is the most abundant circulating steroid in humans, with peak levels between 20 and 30 yr of age, followed by a steady, age-dependent decline. Many metabolic effects, including antiobesity, antidiabetic, and antiaging properties, have been attributed to DHEA.4 In rodents, DHEA attenuated ischemia/reperfusion-induced oxidative stress and renal dysfunction,5 showed beneficial effects in diabetic nephropathy,6,7 and inhibited the age-related development of proteinuria.8 DHEA seems to counteract several adverse effects of excessive glucocorticoid action, including a negative correlation between DHEA concentrations and body mass index, visceral adiposity, and impaired insulin sensi-tivity in elderly individuals9; however, the molecular mechanisms underlying these antigluco-corticoid effects remain unclear.
In peripheral tissues, local glucocorticoid metabolism is mainly controlled by 11β-hydroxysteroid dehydrogenase (11β-HSD1) and 11β-HSD2. 11β-HSD1 catalyzes the reduction of inactive 11-ketoglucocorticoids (cortisone, 11-dehydrocorticosterone) into active 11β-hydroxyglucocorticoids (cortisol, corticosterone).2In vitro, 11β-HSD1 catalyzes both reductase and dehydrogenase reaction, whereas in vivo and in intact cells expressing hexose-6-phosphate dehydrogenase, providing co-substrate NADPH, it predominantly acts as a reductase and is essential for glucocorticoid reactivation in metabolically relevant tissues.10–12 11β-HSD2 acts exclusively as a dehydrogenase using co-substrate NAD+ and has a pivotal role in mineralocorticoid target tissues by protecting mineralocorticoid receptors (MR) from activation by cortisol and in placenta by protecting the fetus from high maternal cortisol.13
Several steroid hormones have been associated with the regulation of 11β-HSD gene expression.14 Homma et al.15 showed that administration of DHEA sulfate decreased BP in spontaneously hypertensive rats. Treated rats had reduced ratios of serum corticosterone to 11-dehydrocorticosterone, and the oxidation of corticosterone was increased in kidneys but decreased in the liver, suggesting that altered 11β-HSD activities contributed to the observed effects; however, these authors did not clearly distinguish between the activities of 11β-HSD1 and 11β-HSD2 or take into account that 11β-HSD1 also functions as a dehydrogenase with NAD+.16 We recently reported reduced 11β-HSD1 expression in response to DHEA in 3T3-L1 adipocytes and in liver and adipose tissue of treated mice.17 We showed that the CCAAT/enhancer-binding protein (C/EBP) family of basic leucin zipper transcription factors C/EBP-α, C/EBP-β, and C/EBP-δ is involved in the DHEA-mediated regulation of 11β-HSD1 expression. C/EBP can act as transcriptional activators as well as repressors.18 C/EBP-α and C/EBP-β were shown to bind directly to the HSD11B1 promoter and act in concert to regulate gene expression in liver cells19 and adipocytes.20 Whether C/EBP might also modulate HSD11B2 gene expression has not been investigated.
Here, we examined the impact of DHEA on 11β-HSD2 expression and activity in cultured cells and in kidneys of Sprague-Dawley rats and C57BL/6J mice. We investigated whether C/EBP are involved in the transcriptional regulation of 11β-HSD2 and compared their effects with those on 11β-HSD1. In particular, we tested whether C/EBP transcription factors might be responsible for the differential regulation of 11β-HSD1 and 11β-HSD2."
DHEA Induces 11β-HSD2 by Acting on CCAAT/Enhancer-Binding Proteins
Enhanced glucocorticoid effects, mainly as a result of locally disturbed glucocorticoid metabolism, contribute to diseases such as hypertension and the metabolic syndrome.1–3 The adrenal steroid hormone precursor dehydroepiandrosterone (DHEA) is the most abundant circulating steroid in humans, with peak levels between 20 and 30 yr of age, followed by a steady, age-dependent decline. Many metabolic effects, including antiobesity, antidiabetic, and antiaging properties, have been attributed to DHEA.4 In rodents, DHEA attenuated ischemia/reperfusion-induced oxidative stress and renal dysfunction,5 showed beneficial effects in diabetic nephropathy,6,7 and inhibited the age-related development of proteinuria.8 DHEA seems to counteract several adverse effects of excessive glucocorticoid action, including a negative correlation between DHEA concentrations and body mass index, visceral adiposity, and impaired insulin sensi-tivity in elderly individuals9; however, the molecular mechanisms underlying these antigluco-corticoid effects remain unclear.
In peripheral tissues, local glucocorticoid metabolism is mainly controlled by 11β-hydroxysteroid dehydrogenase (11β-HSD1) and 11β-HSD2. 11β-HSD1 catalyzes the reduction of inactive 11-ketoglucocorticoids (cortisone, 11-dehydrocorticosterone) into active 11β-hydroxyglucocorticoids (cortisol, corticosterone).2In vitro, 11β-HSD1 catalyzes both reductase and dehydrogenase reaction, whereas in vivo and in intact cells expressing hexose-6-phosphate dehydrogenase, providing co-substrate NADPH, it predominantly acts as a reductase and is essential for glucocorticoid reactivation in metabolically relevant tissues.10–12 11β-HSD2 acts exclusively as a dehydrogenase using co-substrate NAD+ and has a pivotal role in mineralocorticoid target tissues by protecting mineralocorticoid receptors (MR) from activation by cortisol and in placenta by protecting the fetus from high maternal cortisol.13
Several steroid hormones have been associated with the regulation of 11β-HSD gene expression.14 Homma et al.15 showed that administration of DHEA sulfate decreased BP in spontaneously hypertensive rats. Treated rats had reduced ratios of serum corticosterone to 11-dehydrocorticosterone, and the oxidation of corticosterone was increased in kidneys but decreased in the liver, suggesting that altered 11β-HSD activities contributed to the observed effects; however, these authors did not clearly distinguish between the activities of 11β-HSD1 and 11β-HSD2 or take into account that 11β-HSD1 also functions as a dehydrogenase with NAD+.16 We recently reported reduced 11β-HSD1 expression in response to DHEA in 3T3-L1 adipocytes and in liver and adipose tissue of treated mice.17 We showed that the CCAAT/enhancer-binding protein (C/EBP) family of basic leucin zipper transcription factors C/EBP-α, C/EBP-β, and C/EBP-δ is involved in the DHEA-mediated regulation of 11β-HSD1 expression. C/EBP can act as transcriptional activators as well as repressors.18 C/EBP-α and C/EBP-β were shown to bind directly to the HSD11B1 promoter and act in concert to regulate gene expression in liver cells19 and adipocytes.20 Whether C/EBP might also modulate HSD11B2 gene expression has not been investigated.
Here, we examined the impact of DHEA on 11β-HSD2 expression and activity in cultured cells and in kidneys of Sprague-Dawley rats and C57BL/6J mice. We investigated whether C/EBP are involved in the transcriptional regulation of 11β-HSD2 and compared their effects with those on 11β-HSD1. In particular, we tested whether C/EBP transcription factors might be responsible for the differential regulation of 11β-HSD1 and 11β-HSD2."
DHEA Induces 11β-HSD2 by Acting on CCAAT/Enhancer-Binding Proteins
