Primary Cortisol Resistance Accompanied by a Reduction in Glucocorticoid Receptors in Two Members of the Same Family*

Iida, Shinji; Gomi, Masahiro; Moriwaki, Kaname; Itoh, Yoshiharu; Hirobe, Kazuhiko; Matsuzawa, Yūji; Katagiri, Seiji; Yonezawa, Takeshi; Tarui, Seiichiro

doi:10.1210/jcem-60-5-967

Cited by 86 publications

(23 citation statements)

References 11 publications

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“…This is supported by studies describing the absence of Cushingoid features and metabolic abnormalities in hypercortisolemic patients (21) and, conversely, the manifestation of the Cushing's syndrome phenotype in hypocortisolemic patients (22).…”

mentioning

confidence: 69%

Increased Glucocorticoid Receptor Expression in Human Skeletal Muscle Cells May Contribute to the Pathogenesis of the Metabolic Syndrome

et al. 2002

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Altered glucocorticoid hormone action may contribute to the etiology of the metabolic syndrome, but the molecular mechanisms are poorly defined. Tissue sensitivity to glucocorticoid is regulated by expression of the glucocorticoid receptor (GR)-␣ and 11␤-hydroxysteroid dehydrogenase type I (11␤-HSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed GR␣ and 11␤-HSD1 expression in skeletal myoblasts from men (n ‫؍‬ 14) with contrasting levels of insulin sensitivity (euglycemic clamp measurements of insulin-dependent glucose disposal rate), blood pressure, and adiposity. Positive associations were evident between myoblast expression of GR␣ under basal conditions and levels of insulin resistance (r 2 ‫؍‬ 0.34, P < 0.05), BMI (r 2 ‫؍‬ 0.49, P < 0.01), percent body fat (r 2 ‫؍‬ 0.34, P < 0.02), and blood pressure (r 2 ‫؍‬ 0.86, P < 0.001). Similar associations were evident when myoblasts were incubated with physiological levels of cortisol (P < 0.01 for all). Importantly, GR␣ expression was unaffected by variations in in vivo concentrations of insulin, IGF-1, or glucose concentrations. In common with the GR, 11␤-HSD1 expression in myoblasts incubated with physiological concentrations of cortisol in vitro was positively associated with levels of insulin resistance (r 2 ‫؍‬ 0.68, P < 0.001), BMI (r 2 ‫؍‬ 0.63, P < 0.005), and blood pressure (r 2 ‫؍‬ 0.27, P < 0.05). Regulation of GR␣ and 11␤-HSD1 by cortisol was abolished by the GR antagonist RU38486. In summary, our data suggest that raised skeletal muscle cell expression of GR␣ and 11␤-HSD1-mediated regulation of intracellular cortisol may play a fundamental role in mechanisms contributing to the pathogenesis of the metabolic syndrome.

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confidence: 69%

Increased Glucocorticoid Receptor Expression in Human Skeletal Muscle Cells May Contribute to the Pathogenesis of the Metabolic Syndrome

et al. 2002

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“…Primary glucocorticoid resistance due to inherited abnormalities of the glucocorticoid receptor (GR) have been described (Iida et al 1985) but very few cases have been reported worldwide and there are no reports in the literature of IBD patients with primary glucocorticoid resistance or grossly elevated cortisol levels characteristic of this condition. However, most glucocorticoid resistance research on T-lymphocytes and other target inflammatory cells have demonstrated several GR abnormalities as potential mechanisms influencing response to glucocorticoid treatment in several inflammatory conditions.…”

Section: Glucocorticoid Receptor Abnormalities and Glucocorticoid Resmentioning

confidence: 99%

Glucocorticoid resistance in inflammatory bowel disease

Rj¹,

Kelleher²

2003

Journal of Endocrinology

219

122

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Glucocorticoids are potent inhibitors of T cell activation and proinflammatory cytokines and are highly effective treatment for active inflammatory bowel disease (IBD). However, failure to respond, acutely or chronically, to glucocorticoid therapy is a common indication for surgery in IBD, with as many as 50% of patients with Crohn's disease (CD) and approximately 20% of patients with ulcerative colitis (UC) requiring surgery in their lifetime as a result of poor response to glucocorticoids. Studies report that approximately one-third of patients with CD are steroid dependent and one-fifth are steroid resistant while approximately one-quarter of patients with UC are steroid dependent and one-sixth are steroid resistant. While the molecular basis of glucocorticoid resistance has been widely assessed in other inflammatory conditions, the pathophysiology of the glucocorticoid resistance in IBD is poorly understood. Research in IBD suggests that the phenomenon of glucocorticoid resistance is compartmentalised to T-lymphocytes and possibly other target inflammatory cells. This review focuses on three key molecular mechanisms of glucocorticoid resistance in IBD: (i) decreased cytoplasmic glucocorticoid concentration secondary to increased P-glycoprotein-mediated efflux of glucocorticoid from target cells due to overexpression of the multidrug resistance gene (MDR1); (ii) impaired glucocorticoid signaling because of dysfunction at the level of the glucocorticoid receptor; and (iii) constitutive epithelial activation of proinflammatory mediators, including nuclear factor kappa B, resulting in inhibition of glucocorticoid receptor transcriptional activity. In addition, the impact of disease heterogeneity on glucocorticoid responsiveness and recent advances in IBD pharmacogenetics are discussed.

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“…6, and references therein] or decreased receptor content [7]. A direct correlation between the number of GRs and cellular responsiveness to the hormone has been documented in a variety of cell lines [8][9][10][11] as well as in human subjects [12][13][14][15][16][17][18].…”

Section: Glucocorticoidmentioning

confidence: 99%

Homologous Down-Regulation of the Glucocorticoid Receptor Down-Modulates Cellular Hormone Responsiveness in Human Histiocytic Lymphoma U937 Cells.

et al. 1994

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Abstract. One of the determinants of cellular responsiveness to glucocorticoid hormone is the concentration of the receptor protein. It is well-known that cellular receptor levels are down-regulated by the cognate ligands, but the biological significance of this homologous down-regulation of the receptor has not yet been completely understood. We showed that in human histiocytic lymphoma cell line U937 the cellular glucocorticoid receptor was homologously down-regulated by means of both ligand binding and Western immunoblot experiments. Reduction of the receptor was saturable, and the receptor levels tended to return to the levels before treatment after 3-day culture in the presence of the hormone. Next, using the cells which were pretreated with the hormone for 0 to 3 days, hormonal inducibility of the transiently-transfected reporter gene and the inhibitory effect of the hormone on cellular 3-0-methyl glucose uptake were determined.Hormonal inducibility of the reporter gene was progressively reduced, and thereafter tended to be restored, apparently in accordance with the cyclic change in amount of the receptor. The glucose uptake inhibiting effect of the hormone also revealed this cyclic pattern. In summary, in U937 cells glucocorticoid receptor was homologously down-regulated and may play a pivotal role in attenuating hormone responsiveness.

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Primary Cortisol Resistance Accompanied by a Reduction in Glucocorticoid Receptors in Two Members of the Same Family*

Cited by 86 publications

References 11 publications

Increased Glucocorticoid Receptor Expression in Human Skeletal Muscle Cells May Contribute to the Pathogenesis of the Metabolic Syndrome

Increased Glucocorticoid Receptor Expression in Human Skeletal Muscle Cells May Contribute to the Pathogenesis of the Metabolic Syndrome

Glucocorticoid resistance in inflammatory bowel disease

Homologous Down-Regulation of the Glucocorticoid Receptor Down-Modulates Cellular Hormone Responsiveness in Human Histiocytic Lymphoma U937 Cells.

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