Optimization of Stress Response Through the Nuclear Receptor-mediated Cortisol Signalling Network

Overview

Journal Nat Commun

Specialty Biology

Date 2013 May 9

PMID 23653204

Citations 14

Authors

Alexey Kolodkin

Nilgun Sahin

Anna Phillips

Steve R Hood

Frank J Bruggeman

Hans V Westerhoff

Nick Plant

Affiliations

Soon will be listed here.

Abstract

It is an accepted paradigm that extended stress predisposes an individual to pathophysiology. However, the biological adaptations to minimize this risk are poorly understood. Using a computational model based upon realistic kinetic parameters we are able to reproduce the interaction of the stress hormone cortisol with its two nuclear receptors, the high-affinity glucocorticoid receptor and the low-affinity pregnane X-receptor. We demonstrate that regulatory signals between these two nuclear receptors are necessary to optimize the body's response to stress episodes, attenuating both the magnitude and duration of the biological response. In addition, we predict that the activation of pregnane X-receptor by multiple, low-affinity endobiotic ligands is necessary for the significant pregnane X-receptor-mediated transcriptional response observed following stress episodes. This integration allows responses mediated through both the high and low-affinity nuclear receptors, which we predict is an important strategy to minimize the risk of disease from chronic stress.

Citing Articles

Transcriptomics Unveil Canonical and Non-Canonical Heat Shock-Induced Pathways in Human Cell Lines.

Reinschmidt A, Solano L, Chavez Y, Hulsy W, Nikolaidis N Int J Mol Sci. 2025; 26(3).

PMID: 39940831 PMC: 11816735. DOI: 10.3390/ijms26031057.

Pregnane X Receptor and the Gut-Liver Axis: A Recent Update.

Dutta M, Lim J, Cui J Drug Metab Dispos. 2021; 50(4):478-491.

PMID: 34862253 PMC: 11022899. DOI: 10.1124/dmd.121.000415.

Expression dynamics of pregnane X receptor-controlled genes in 3D primary human hepatocyte spheroids.

Smutny T, Bernhauerova V, Smutna L, Duintjer Tebbens J, Pavek P Arch Toxicol. 2021; 96(1):195-210.

PMID: 34689256 DOI: 10.1007/s00204-021-03177-y.

Adrenergic and Glucocorticoid Receptors in the Pulmonary Health Effects of Air Pollution.

Hodge M, Henriquez A, Kodavanti U Toxics. 2021; 9(6).

PMID: 34200050 PMC: 8226814. DOI: 10.3390/toxics9060132.

4-Hydroxycholesterol Signals From the Liver to Regulate Peripheral Cholesterol Transporters.

Salonurmi T, Nabil H, Ronkainen J, Hyotylainen T, Hautajarvi H, Savolainen M Front Pharmacol. 2020; 11:361.

PMID: 32292343 PMC: 7118195. DOI: 10.3389/fphar.2020.00361.

References

Plant N, GIBSON G, Moore D . Regulation of the CYP3A4 gene by hydrocortisone and xenobiotics: role of the glucocorticoid and pregnane X receptors. Drug Metab Dispos. 2000; 28(5):493-6. View

Conrad C . A critical review of chronic stress effects on spatial learning and memory. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 34(5):742-55. DOI: 10.1016/j.pnpbp.2009.11.003. View

Kitano H . Biological robustness. Nat Rev Genet. 2004; 5(11):826-37. DOI: 10.1038/nrg1471. View

Plant N, Aouabdi S . Nuclear receptors: the controlling force in drug metabolism of the liver?. Xenobiotica. 2009; 39(8):597-605. DOI: 10.1080/00498250903098218. View

N Kolodkin A, Bruggeman F, Plant N, Mone M, Bakker B, Campbell M . Design principles of nuclear receptor signaling: how complex networking improves signal transduction. Mol Syst Biol. 2010; 6:446. PMC: 3018161. DOI: 10.1038/msb.2010.102. View

Rigaud G, Roux J, Pictet R, Grange T . In vivo footprinting of rat TAT gene: dynamic interplay between the glucocorticoid receptor and a liver-specific factor. Cell. 1991; 67(5):977-86. DOI: 10.1016/0092-8674(91)90370-e. View

El-Sankary W, Bombail V, Gibson G, Plant N . Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein: DNA interaction distinct from the pregnane X receptor response element. Drug Metab Dispos. 2002; 30(9):1029-34. DOI: 10.1124/dmd.30.9.1029. View

Shively C, Register T, Clarkson T . Social stress, visceral obesity, and coronary artery atherosclerosis: product of a primate adaptation. Am J Primatol. 2009; 71(9):742-51. PMC: 3970187. DOI: 10.1002/ajp.20706. View

Arda H, Taubert S, MacNeil L, Conine C, Tsuda B, Van Gilst M . Functional modularity of nuclear hormone receptors in a Caenorhabditis elegans metabolic gene regulatory network. Mol Syst Biol. 2010; 6:367. PMC: 2890327. DOI: 10.1038/msb.2010.23. View

10.

Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Backman M . Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U S A. 1998; 95(21):12208-13. PMC: 22810. DOI: 10.1073/pnas.95.21.12208. View

11.

Huizenga N, de Herder W, Koper J, de Lange P, v D Lely A, Brinkmann A . Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome. Eur J Endocrinol. 2000; 142(5):472-6. DOI: 10.1530/eje.0.1420472. View

12.

Gibson G, Phillips A, Aouabdi S, Plant K, Plant N . Transcriptional regulation of the human pregnane-X receptor. Drug Metab Rev. 2006; 38(1-2):31-49. DOI: 10.1080/03602530600569810. View

13.

Aouabdi S, Gibson G, Plant N . Transcriptional regulation of the PXR gene: identification and characterization of a functional peroxisome proliferator-activated receptor alpha binding site within the proximal promoter of PXR. Drug Metab Dispos. 2005; 34(1):138-44. DOI: 10.1124/dmd.105.006064. View

14.

Oakley R, Cidlowski J . Homologous down regulation of the glucocorticoid receptor: the molecular machinery. Crit Rev Eukaryot Gene Expr. 1993; 3(2):63-88. View

15.

Handschin C, Blattler S, Roth A, Looser R, Oscarson M, Kaufmann M . The evolution of drug-activated nuclear receptors: one ancestral gene diverged into two xenosensor genes in mammals. Nucl Recept. 2004; 2(1):7. PMC: 524364. DOI: 10.1186/1478-1336-2-7. View

16.

Pan D, Kocherginsky M, Conzen S . Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer Res. 2011; 71(20):6360-70. PMC: 3514452. DOI: 10.1158/0008-5472.CAN-11-0362. View

17.

Masson M, Collins L, Carpenter L, Graf M, Ryan P, Bourdi M . Pathologic role of stressed-induced glucocorticoids in drug-induced liver injury in mice. Biochem Biophys Res Commun. 2010; 397(3):453-8. PMC: 2897926. DOI: 10.1016/j.bbrc.2010.05.126. View

18.

Blumberg B, Sabbagh Jr W, Juguilon H, Bolado Jr J, van Meter C, Ong E . SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev. 1998; 12(20):3195-205. PMC: 317212. DOI: 10.1101/gad.12.20.3195. View

19.

Hoops S, Sahle S, Gauges R, Lee C, Pahle J, Simus N . COPASI--a COmplex PAthway SImulator. Bioinformatics. 2006; 22(24):3067-74. DOI: 10.1093/bioinformatics/btl485. View

20.

Anagnostis P, Athyros V, Tziomalos K, Karagiannis A, Mikhailidis D . Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab. 2009; 94(8):2692-701. DOI: 10.1210/jc.2009-0370. View