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Post by Max on Jul 12, 2005 18:21:30 GMT -5
Receptor expression and metabolism
Cortisol binds to the human glucocorticoid receptor (hGR) [1]. In humans, hGR is found to exist in two isoforms, receptor protein a (94kDa) and b (91kDa) [4]. 11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of 11-dehydrocorticosterone to its active form corticosterone in rodents (or cortisone to cortisol in humans). The reductive reaction of the 11-keto to 11-hydroxyl is the pivotal switch in the activation of glucocorticoids [2, 3 and more].
C/EBPalpha is a potent activator of the 11beta-HSD1 gene in hepatoma cells and that mice deficient in C/EBPalpha have reduced hepatic 11beta-HSD1 expression. In contrast, C/EBPbeta is a relatively weak activator of 11beta-HSD1 transcription in hepatoma cells and attenuates C/EBPalpha induction, and mice that lack C/EBPbeta have increased hepatic 11beta-HSD1 mRNA. The 11beta-HSD1 promoter (between -812 and +76) contains 10 C/EBP binding sites, and mutation of the promoter proximal sites decreases the C/EBP inducibility of the promoter. One site encompasses the transcription start, and both C/EBPalpha and C/EBPbeta are present in complexes formed by liver nuclear proteins at this site. The regulation of 11beta-HSD1 expression, and hence intracellular glucocorticoid levels, by members of the C/EBP family provides a mechanism for cross-talk between the C/EBP family of transcription factors and the glucocorticoid signaling pathway [5].
11beta-HSD-1 is particularly expressed in adipocytes and liver and appears to be causally linked to the development of type 2 diabetes and the metabolic syndrome. Liver X receptor (LXR)-alpha and -beta are nuclear oxysterol receptors whose key role in lipid metabolic regulation has recently been established. Adipocytes derived from 3T3-L1 cells and mouse embryonic fibroblasts in vitro with synthetic or natural LXR agonists decreases mRNA expression of 11beta-HSD-1 by approximately 50%, paralleled by a significant decline in 11beta-HSD-1 enzyme activity [3].
A clinical vitamin A deficiency is here suggested to be a result after a (Ro)accutane exposure in human subjects, partly due to TGF-beta1 induced megalin/cubulin inhibition leading to severe failure in the uptake and recirculation of retinol binding protein (RBP) see sections about vitamin A and D.
Hydrocortisone (HCT)
The retinoic acid receptor cDNA bears a 15% homology to the hydrocortisone (HCT) receptor, which thus here is suggested to be one additive pathway of (Ro)accutane induced significant interference with the GH/IGF-axis. In rat pituitary GH3 cells, hydrocortisone is known to stimulate GH secretion. Retinoic acid <1 microM stimulated growth hormone secretion by 220%. 50 nM HCT stimulated GH secretion 3,5 times and in synergy GH secretion was stimulated seven times. Retinoic acid selectively stimulates basal and HCT-induced GH secretion and mRNA levels in these cells in a dose- and time-dependent manner [6].
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Post by Max on Jul 12, 2005 18:21:50 GMT -5
Conclusions
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Post by Max on Jul 12, 2005 18:22:49 GMT -5
References:
[1] von Langen J, Fritzemeier KH, Diekmann S, Hillisch A. Molecular basis of the interaction specificity between the human glucocorticoid receptor and its endogenous steroid ligand cortisol. (2005)Chembiochem. Jun;6(6):1110-8. [2] Zhang J, Osslund TD, Plant MH, Clogston CL, Nybo RE, Xiong F, Delaney JM, Jordan SR. Crystal structure of murine 11 beta-hydroxysteroid dehydrogenase 1: an important therapeutic target for diabetes. (2005) Biochemistry. May 10;44(18):6948-57. [3] Liver X receptors downregulate 11beta-hydroxysteroid dehydrogenase type 1 expression and activity. Stulnig TM, Oppermann U, Steffensen KR, Schuster GU, Gustafsson JA. (2002) Diabetes. Aug;51(8):2426-33. [4] Yudt MR, Cidlowski JA. Molecular identification and characterization of a and b forms of the glucocorticoid receptor. Mol Endocrinol. 2001 Jul;15(7):1093-103. [5] Williams LJ, Lyons V, MacLeod I, Rajan V, Darlington GJ, Poli V, Seckl JR, Chapman KE. C/EBP regulates hepatic transcription of 11beta -hydroxysteroid dehydrogenase type 1. A novel mechanism for cross-talk between the C/EBP and glucocorticoid signaling pathways. (2000) J Biol Chem. Sep 29;275(39):30232-9. [6] Morita S, Fernandez-Mejia C, Melmed S. Retinoic acid selectively stimulates growth hormone secretion and messenger ribonucleic acid levels in rat pituitary cells. (1989) Endocrinology. May;124(5):2052-6.
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Post by Max on Jul 12, 2005 18:55:53 GMT -5
Acta Biochim Pol. 2004;51(4):907-17. Related Articles, Links
Inhibition of CYP17 expression by adrenal androgens and transforming growth factor beta in adrenocortical cells.
Biernacka-Lukanty JM, Lehmann TP, Trzeciak WH.
Department of Biochemistry and Molecular Biology, University of Medical Sciences, Poznan, Poland.
Cytochrome P450c17, encoded by the CYP17 gene, is a component of the 17alpha-hydroxylase/17,20-lyase enzyme complex essential for production of adrenal glucocorticoids and androgens as well as gonadal androgens. The expression of CYP17 in adrenocortical cells is stimulated by corticotropin (ACTH) via the signal transduction pathway involving cAMP and protein kinase A (PKA). Thus, in addition to glucocorticoids, ACTH stimulates formation of adrenal androgens, which are known to induce transforming growth factor beta (TGF-beta) secretion. TGF-b in turn inhibits steroid hormone output by attenuating both basal and ACTH-dependent expression of CYP17. The present study revealed that treatment of bovine and human H295R adrenocortical cells with androgens resulted in a decrease in the basal level of CYP17 transcript and cortisol secretion, without affecting forskolin-stimulated levels. We also demonstrated that in H295R cells TGF-beta inhibited both basal and forskolin-stimulated accumulation of CYP17 mRNA. Determination of promoter activity, directing luciferase reporter gene expression in H295R cells transfected with deletion fragments of bovine CYP17 promoter, indicated that the -483 to -433 bp fragment of the promoter was necessary for the inhibitory action of TGF-beta on CYP17 expression. It is concluded that in bovine and human adrenocortical cells, androgens inhibit basal CYP17 expression probably at the transcriptional level and independently of the effect of TGF-beta.
PMID: 15625562 [PubMed - in process]
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Post by Max on Jul 13, 2005 7:49:29 GMT -5
Chembiochem. 2005 Jun;6(6):1110-8. Related Articles, Links
Molecular basis of the interaction specificity between the human glucocorticoid receptor and its endogenous steroid ligand cortisol.
von Langen J, Fritzemeier KH, Diekmann S, Hillisch A.
Institute for Molecular Biotechnology, Beutenbergstrasse 11, 07745 Jena, Germany.
We analyzed the binding of five steroids to the human glucocorticoid receptor (hGR) experimentally as well as theoretically. In vitro, we measured the binding affinity of aldosterone, cortisol, estradiol, progesterone, and testosterone to hGR in competition with the ligand dexamethasone. The binding affinity relative to the endogenous ligand cortisol (100%) is reduced for progesterone (22%) and aldosterone (20%) and is very weak for testosterone (1.5%) and estradiol (0.2%). In parallel, we constructed a homology model of the hGR ligand-binding domain (LBD) based on the crystal structure of the human progesterone receptor (hPR). After docking the five steroids into the hGR model ligand-binding pocket, we performed five separate 4-ns molecular dynamics (MD) simulations with these complexes in order to study the complex structures. We calculated the binding affinities with two different approaches (MM/PBSA, FlexX) and compared them with the values of the experimentally determined relative binding affinities. Both theoretical methods allowed discrimination between strongly and weakly binding ligands and recognition of cortisol as the endogenous ligand of the hGR in silico. Cortisol binds most strongly due to a nearly perfect steric and electrostatic complementarity with the hGR binding pocket. Chemically similar ligands such as estradiol, testosterone, and progesterone also fit into the hGR binding pocket, but they are unable to form all those contacts with the amino acids of the protein that are necessary to yield a stable, transcriptionally active receptor conformation. Our analysis thus explains the selectivity of the human glucocorticoid receptor for its endogenous ligand cortisol at a molecular level.
PMID: 15883974 [PubMed - in process]
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Post by Max on Jul 13, 2005 7:56:08 GMT -5
Metabolism. 2005 May;54(5):584-9. Related Articles, Links
Corticosteroid-binding globulin affects the relationship between circulating adiponectin and cortisol in men and women.
Fernandez-Real JM, Pugeat M, Lopez-Bermejo A, Bornet H, Ricart W.
Diabetes, Endocrinology and Nutrition Research Unit, Dr. Josep Trueta University Hospital of Girona, Carretera de Francia s/n, 17007 Girona, Spain. uden.jmfernandezreal@htrueta.scs.es
Inflammatory pathways are increasingly recognized to be tightly associated with insulin resistance in humans. The promoter region of the adiponectin gene--Apm1--encompasses consensus sequences for glucocorticosteroid receptor responsive element. Dexamethasone induced downregulation of adiponectin secretion in vitro, whereas prednisolone administration increased circulating adiponectin concentrations. As previous studies have demonstrated an inverse relationship between corticosteroid-binding globulin (CBG), body mass index, and insulin resistance, we studied whether CBG could explain cortisol-to-adiponectin relationship. One hundred twenty-two healthy subjects were enrolled in a cross-sectional study. Plasma CBG and serum cortisol concentration were measured by radioimmunoassay. The cortisol-to-CBG ratio was used to calculate free cortisol. An RIA kit (Linco Research, St Louis, MO) was used to measure adiponectin levels. Insulin resistance was calculated using the homeostatis model of assessment (HOMA) value. Circulating adiponectin was associated with serum CBG ( r = 0.38, P < .00001), both in men ( r = 0.26, P = .03, n = 79) and women ( r = 0.48, P = .003, n = 43), and with insulin resistance (HOMA index) ( r = -0.30, P < .0001) in both. Free cortisol correlated negatively with adiponectin only in women ( r = -0.32, P = .04), but not in men ( r = 0.01, P = .89). Serum CBG concentration was significantly lower among men in the lowest quartile of adiponectin when compared with the remaining subjects (37.3 +/- 5.7 vs 40.6 +/- 5.1, P = .016), whereas men in the highest quartile of adiponectin showed significantly increased free cortisol index (14.2 +/- 3.3 vs 12.2 +/- 3.1, P = .039). Women in the lowest quartile of adiponectin also displayed significantly lower CBG concentration than that present in the remaining subjects (38.6 +/- 6.9 vs 44.4 +/- 5.5, P = .016), whereas free cortisol index was not significantly different across adiponectin quartiles ( P = .1). In a stepwise regression analysis, body mass index ( P = .0011), CBG ( P = .0047), and sex ( P = .04) contributed to 15%, 8%, and 3%, respectively, of adiponectin variance. Using CBG as dependent variable, both adiponectin ( P = .0002) and fasting cortisol ( P = .019) contributed to 14% and 4%, respectively, of CBG variance. In summary, circulating adiponectin, CBG concentration, and fasting cortisol were significantly interrelated in healthy subjects. A significant sexual dimorphism exists in this association.
PMID: 15877287 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 13, 2005 8:13:14 GMT -5
Mol Endocrinol. 2005 Jan;19(1):52-64. Epub 2004 Sep 30. Related Articles, Links
The human glucocorticoid receptor (hGR) beta isoform suppresses the transcriptional activity of hGRalpha by interfering with formation of active coactivator complexes.
Charmandari E, Chrousos GP, Ichijo T, Bhattacharyya N, Vottero A, Souvatzoglou E, Kino T.
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Room 9D42, Bethesda, Maryland 20892-1583, USA. charmane@mail.nih.gov
The human glucocorticoid receptor (hGR) beta, a splicing variant of the classic receptor hGRalpha, functions as a dominant-negative inhibitor of hGRalpha. We explored the mechanism(s) underlying this effect of hGRbeta by evaluating the interactions of this isoform with known steroid receptor coactivators. We found that hGRbeta suppressed the transcriptional activity of both activation function (AF)-1 and AF-2 of hGRalpha, indicating that hGRbeta may exert its dominant-negative effect by affecting the function of coactivators that are attracted to these transactivation domains. hGRbeta bound to one of the p160 coactivators, the glucocorticoid receptor-interacting protein 1 (GRIP1) via its preserved AF-1 but not via its defective AF-2 in vitro. In a chromatin immunoprecipitation assay, hGRbeta prevented coprecipitation of GRIP1 with hGRalpha tethered to glucocorticoid response elements of the endogenous tyrosine aminotransferase promoter, whereas deletion of the AF-1 of hGRbeta abolished this effect. In further experiments, overexpression of GRIP1 attenuated the suppressive effect of hGRbeta on hGRalpha-mediated transactivation of the mouse mammary tumor virus promoter. Competition for binding to glucocorticoid response elements or heterodimerization with hGRalpha via the D loop dimerization interface occurred, but they were not necessary for the suppressive effect of hGRbeta on the transcriptional activity of hGRalpha. Our findings suggest that hGRbeta suppresses the transcriptional activity of hGRalpha by competing with hGRalpha for binding to GRIP1, and possibly other p160 coactivators, through its preserved AF-1. These findings suggest that participation of hGRbeta in the formation of a coactivator complex renders this complex ineffective.
PMID: 15459252 [PubMed - indexed for MEDLINE]
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Post by Max on Jul 24, 2005 8:53:36 GMT -5
Mol Cell Endocrinol. 2004 Jul 30;222(1-2):33-40. Related Articles, Links
Regulation of human glucocorticoid receptor gene transcription by Sp1 and p53.
Suehiro T, Kaneda T, Ikeda Y, Arii K, Kumon Y, Hashimoto K.
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan. suehirot@med.kochi-u.ac.jp
The human glucocorticoid receptor (hGR) gene has several GC boxes in the promoter 1C region. We studied the effects of Sp1 and p53 on promoter 1C in HepG2 and HEK293 cells using luciferase (Lu) reporter assay. The results showed that the first GC box upstream of the transcription site activated the hGR promoter and over-expression of Sp1 obviously enhanced the activity. A mutant Lu-hGR vector, whose first GC box was defective, lost promoter activity nearly completely. Further, over-expression of p53 strongly suppressed the stimulating effect of Sp1 on hGR promoter activity. We concluded that Sp1 activates the hGR gene promoter, at least in part, by acting on the first GC box in promoter 1C, while p53 suppresses the transactivation by Sp1. These phenomena, demonstrated in cultured cells, may be important for the expression of hGR in vivo.
PMID: 15249123 [PubMed - indexed for MEDLINE]
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