DHEA Induces 11β-HSD2 by Acting on CCAAT/Enhancer-Binding Proteins

Abstract

11␤-Hydroxysteroid dehydrogenase (11␤-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 11␤-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-␣ (C/EBP-␣) and C/EBP-␤ regulated HSD11B2 transcription and that DHEA likely modulated the transcription of 11␤-HSD2 in a phosphatidylinositol-3 kinase/Akt-dependent manner by increasing C/EBP-␤ mRNA and protein expression. Moreover, it is shown that C/EBP-␣ and C/EBP-␤ differentially regulate the expression of 11␤-HSD1 and 11␤-HSD2. In conclusion, DHEA induces a shift from 11␤-HSD1 to 11␤-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 sensitivity in elderly individuals 9 ; however, the molecular mechanisms underlying these antiglucocorticoid effects remain unclear.In peripheral tissues, local glucocorticoid metabolism is mainly controlled by 11␤-hydroxysteroid dehydrogenase (11␤-HSD1) and 11␤-HSD2. 11␤-HSD1 catalyzes the reduction of inactive 11-ketoglucocorticoids (cortisone, 11-dehydrocorticosterone) into active 11␤-hy-

Novel regulation of 25‐hydroxyvitamin D3 24‐hydroxylase (24(OH)ase) transcription by glucocorticoids: Cooperative effects of the glucocorticoid receptor, C/EBPβ, and the Vitamin D receptor in 24(OH)ase transcription

“…In addition to cooperative effects between GR and C/EBP in the regulation of gene transcription, glucocorticoids have an effect by inducing some of the C/EBP isoforms. Glucocorticoids have been shown to regulate C/EBPs in different tissues [McCarthy et al, 2000;Delany et al, 2001;Roesler, 2001;Balazs et al, 2008]. Similar to our findings, previous studies have also indicated an induction of C/EBPb (but not C/EBPa) by glucocorticoids in osteoblasts and kidney [McCarthy et al, 2000;Delany et al, 2001;Balazs et al, 2008].…”

Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma

“…The transcription factor CCAAT/enhancer-binding protein C/EBP family is a key mediator of metabolic and inflammatory signalling. It has been reported that dehydroepiandrosterone caused the upregulation of C/EBP-b but did not affect C/EBP-a, whereas C/EBP-a is a strong activator of 11b-HSD1, and C/EBP-b acts in an opposite way and preferentially stimulates 11b-HSD2 expression 37 . Notably, dehydroepiandrosterone-mediated stimulation of 11b-HSD2 involves the activation of phosphoinositide 3-kinase (PI3K)/Akt pathway.…”

Dietary Fructose and Glucose: The Multifacetted Aspects of Their Metabolism and Implication for Human Health

“…An increased 11β-HSD1 expression and activity was observed in mouse 3T3-L1 adipocytes that were cultivated in medium containing fructose as the only carbohydrate source instead of glucose [35]. As a possible explanation for the elevated expression, an increased ratio of the transcription factors C/EBPα to C/EBPβ, reported earlier to be involved in the transcriptional regulation of 11β-HSD1 [138,139], was detected. Moreover, 3T3-L1 adipocytes differentiated in fructose containing medium had elevated expression of GLUT5, thus further enhancing fructose uptake and stimulating 11β-HSD1 expression and activity.…”

“…TNF-α promotes ceramide and FFAs release in systemic circulation [136,137], causing insulin resistance of peripheral tissues and organs [60,138]. TNF-α induces IRS-1(Ser 307 ) phosphorylation to decrease insulin sensitivity in adipose tissue [28,139]. A series of serine kinases, including ERK, c-JNK and p38 MAPK [39] can sense lipid metabolites, and inflammatory cytokines in adipocytes and skeletal muscle cells, the activation of which under TNF-α further disturbs the functions of local tissues and organs [139].…”

“…TNF-α induces IRS-1(Ser 307 ) phosphorylation to decrease insulin sensitivity in adipose tissue [28,139]. A series of serine kinases, including ERK, c-JNK and p38 MAPK [39] can sense lipid metabolites, and inflammatory cytokines in adipocytes and skeletal muscle cells, the activation of which under TNF-α further disturbs the functions of local tissues and organs [139]. IL-6 negatively affects insulin signaling to increase glucose uptake in skeletal muscle and suppress glucose production in liver [140].…”