Tissue-specific glucocorticoid action: a family affair.
Ontology highlight
ABSTRACT:
SUBMITTER: Gross KL
PROVIDER: S-EPMC2720031 | biostudies-literature | 2008 Nov
REPOSITORIES: biostudies-literature
Publications
Tissue-specific glucocorticoid action: a family affair.
Gross Katherine L KL Cidlowski John A JA
Trends in endocrinology and metabolism: TEM 20080919 9
Glucocorticoids exert a wide variety of physiological and pathological responses, most of which are mediated by the ubiquitously expressed glucocorticoid receptor (GR). The glucocorticoid response varies among individuals, as well as within tissues from the same individual, and this phenomenon can be partially explained through understanding the process of generating bioavailable ligand and the molecular heterogeneity of GR. This review focuses on the recent advances in our understanding of prer ...[more]
Similar Datasets
Project description:Glucocorticoid action on target tissues is determined by the density of "nuclear" receptors and intracellular metabolism by the two isozymes of 11?-hydroxysteroid dehydrogenase (11?-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11?-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11?-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11?-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11?-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11?-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11?-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11?-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11?-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11?-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental "programming." The role of 11?-HSD2 as a marker of programming is being explored. The 11?-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.
| S-EPMC3962546 | biostudies-literature
Project description:Background and objectivesMidlife adults are a "pivot" generation, responding to parents' and grown children's problems. Yet, some midlife adults may have families where multiple members suffer sorrows, whereas other midlife adults may have families with few problems. This study examined: (a) typologies of problems across generations and (b) associations between profiles of problems and midlife adults' well-being.Research design and methodsMidlife adults (N = 633) reported their own, each parent's (n = 868), and grown child's (n = 1,785) physical (e.g., injury, cancer), psychological (e.g., anxiety, addiction), and lifestyle problems (e.g., divorce, job loss), and parents' functional disabilities. Midlife adults reported their own depressive symptoms.ResultsLatent profile analysis revealed four family typologies: (a) lowest problems across generations (n = 364), (b) offspring and midlife adult moderate problems, parent high physical problems and disability (n = 165), (c) offspring and parent moderate problems (n = 90), and (d) offspring highest problems (n = 14). Midlife adults in the lowest problems group (Profile a) reported higher income and fewer depressive symptoms than midlife adults in the other groups.Discussion and implicationsMidlife adults cope with challenges when grown children or parents suffer problems, and their well-being may suffer as a result. In this study, regardless of the profile, higher problems in either generation were associated with more depressive symptoms for midlife adults.
| S-EPMC6215460 | biostudies-literature
Project description:Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity.
| S-EPMC7274539 | biostudies-literature
Project description:Glucocorticoids (GCs) are effective drugs, but their clinical use is compromised by severe side effects including hyperglycemia, hyperlipidemia and obesity. They bind to the Glucocorticoid Receptor (GR), which acts as a transcription factor. The activation of metabolic genes by GR is thought to underlie these adverse effects. We identify the bHLH factor E47 as a modulator of GR target genes. Using mouse genetics, we find that E47 is required for the regulation of hepatic glucose and lipid metabolism by GR, and that loss of E47 prevents the development of hyperglycemia and hepatic steatosis in response to GCs. Here we show that E47 and GR co-occupy metabolic promoters and enhancers. E47 is needed for the efficient recruitment of GR and coregulators such as Mediator to chromatin. Altogether, our results illustrate how GR and E47 regulate hepatic metabolism, and might provide an entry point for novel therapies with reduced side effects.
| S-EPMC6338785 | biostudies-literature
Project description:The tumor suppression activity of p53 is frequently impaired in cancers even when a wild-type copy of the gene is still present, suggesting that a dominant-negative effect is exerted by some of p53 mutants and isoforms. p63 and p73, which are related to p53, have also been reported to be subjected to a similar loss of function, suggesting that a dominant-negative interplay might happen between p53, p63 and p73. However, to which extent p53 hotspot mutants and isoforms of p53, p63 and p73 are able to interfere with the tumor suppressive activity of their siblings as well as the underlying mechanisms remain undeciphered. Using yeast, we showed that a dominant-negative effect is widely spread within the p53/p63/p73 family as all p53 loss-of-function hotspot mutants and several of the isoforms of p53 and p73 tested exhibit a dominant-negative potential. In addition, we found that this dominant-negative effect over p53 wild-type is based on tetramer poisoning through the formation of inactive hetero-tetramers and does not rely on a prion-like mechanism contrary to what has been previously suggested. We also showed that mutant p53-R175H gains the ability to inhibit p63 and p73 activity by a mechanism that is only partially based on tetramerization.
| S-EPMC5342497 | biostudies-literature
Project description: Not available
| S-EPMC7395263 | biostudies-literature
Project description:ObjectiveCarbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states.MethodsThe actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding.Results20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20β-DHB and absent in female mice with higher baseline adipose 20β-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding.ConclusionsCarbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice.
| S-EPMC8095185 | biostudies-literature
Project description:For several decades, glucocorticoids have been used empirically to treat rapid progressive GN. It is commonly assumed that glucocorticoids act primarily by dampening the immune response, but the mechanisms remain incompletely understood. In this study, we inactivated the glucocorticoid receptor (GR) specifically in kidney epithelial cells using Pax8-Cre/GRfl/fl mice. Pax8-Cre/GRfl/fl mice did not exhibit an overt spontaneous phenotype. In mice treated with nephrotoxic serum to induce crescentic nephritis (rapidly progressive GN), this genetic inactivation of the GR in kidney epithelial cells exerted renal benefits, including inhibition of albuminuria and cellular crescent formation, similar to the renal benefits observed with high-dose prednisolone in control mice. However, genetic inactivation of the GR in kidney epithelial cells did not induce the immunosuppressive effects observed with prednisolone. In vitro, prednisolone and the pharmacologic GR antagonist mifepristone each acted directly on primary cultures of parietal epithelial cells, inhibiting cellular outgrowth and proliferation. In wild-type mice, pharmacologic treatment with the GR antagonist mifepristone also attenuated disease as effectively as high-dose prednisolone without the systemic immunosuppressive effects. Collectively, these data show that glucocorticoids act directly on activated glomerular parietal epithelial cells in crescentic nephritis. Furthermore, we identified a novel therapeutic approach in crescentic nephritis, that of glucocorticoid antagonism, which was at least as effective as high-dose prednisolone with potentially fewer adverse effects.
| S-EPMC5407712 | biostudies-literature
Project description:Inflammation is a common denominator of diseases. The complement system, an intrinsic part of the innate immune system, is a key driver of inflammation in numerous disorders. Recently, a family of proteins has been suggested to be of vital importance in conditions characterized by complement dysregulation: the human Factor H (FH) family. This group of proteins consists of FH, Factor H-like protein 1 and five Factor H-related proteins. The FH family has been linked to infectious, vascular, eye, kidney and autoimmune diseases. In contrast to FH, the functions of the other highly homologous proteins are largely unknown and, hence, their role in the different disease-specific pathogenic mechanisms remains elusive. In this perspective review, we address the major challenges ahead in this emerging area, including 1) the controversies about the functional roles of the FH protein family, 2) the discrepancies in quantification of the FH protein family, 3) the unmet needs for validated tools and 4) limitations of animal models. Next, we also discuss the opportunities that exist for the immunology community. A strong multidisciplinary approach is required to solve these obstacles and is only possible through interdisciplinary collaboration between biologists, chemists, geneticists and physicians. We position this review in light of our own perspective, as principal investigators of the SciFiMed Consortium, a consortium aiming to create a comprehensive analytical system for the quantitative and functional assessment of the entire FH protein family.
| S-EPMC8044877 | biostudies-literature
Project description:DEAD-box proteins are characterized by nine conserved motifs. According to these criteria, several hundreds of these proteins can be identified in databases. Many different DEAD-box proteins can be found in eukaryotes, whereas prokaryotes have small numbers of different DEAD-box proteins. DEAD-box proteins play important roles in RNA metabolism, and they are very specific and cannot mutually be replaced. In vitro, many DEAD-box proteins have been shown to have RNA-dependent ATPase and ATP-dependent RNA helicase activities. From the genetic and biochemical data obtained mainly in yeast, it has become clear that these proteins play important roles in remodeling RNP complexes in a temporally controlled fashion. Here, I shall give a general overview of the DEAD-box protein family.
| S-EPMC1616962 | biostudies-literature