In April 2016 Manchester eScholar was replaced by the University of Manchester’s new Research Information Management System, Pure. In the autumn the University’s research outputs will be available to search and browse via a new Research Portal. Until then the University’s full publication record can be accessed via a temporary portal and the old eScholar content is available to search and browse via this archive.

Related resources

Full-text held externally

University researcher(s)

Serum cholesterol selectively regulates glucocorticoid sensitivity through activation of JNK.

Yang, Nan; Caratti, Giorgio; Ince, Louise M; Poolman, Toryn M; Trebble, Peter J; Holt, Cathy M; Ray, David W; Matthews, Laura C

The Journal of endocrinology. 2014;223(2):155-66.

Access to files

Full-text and supplementary files are not available from Manchester eScholar. Full-text is available externally using the following links:

Full-text held externally

Abstract

Glucocorticoids (Gc) are potent anti-inflammatory agents with wide clinical application. We have previously shown that increased serum concentration significantly attenuates regulation of a simple Gc-responsive reporter. We now find that glucocorticoid receptor (GR) regulation of some endogenous transactivated but not transrepressed genes is impaired, suggesting template specificity. Serum did not directly affect GR expression, activity or trafficking, implicating GR crosstalk with other signalling pathways. Indeed, a JNK inhibitor completely abolished the serum effect. We identified the Gc modulating serum component as cholesterol. Cholesterol loading mimicked the serum effect, which was readily reversed by JNK inhibition. Chelation of serum cholesterol with methyl-β-cyclodextrin or inhibition of cellular cholesterol synthesis with simvastatin potentiated the Gc response. To explore the effect in vivo we used ApoE(-/-) mice, a model of hypercholesterolaemia. Consistent with our in vitro studies, we find no impact of elevated cholesterol on the expression of GR, or on the hypothalamic-pituitary-adrenal axis, measured by dexamethasone suppression test. Instead we find selective Gc resistance on some hepatic target genes in ApoE(-/-) mice. Therefore, we have discovered an unexpected role for cholesterol as a selective modulator of Gc action in vivo. Taken together these findings reveal a new environmental constraint on Gc action with relevance to both inflammation and cancer.

Bibliographic metadata

Type of resource:
Content type:
Publication type:
Published date:
Abbreviated journal title:
ISSN:
Place of publication:
England
Volume:
223
Issue:
2
Pagination:
155-66
Digital Object Identifier:
10.1530/JOE-14-0456
Pubmed Identifier:
25161081
Pii Identifier:
JOE-14-0456
Access state:
Active

Institutional metadata

University researcher(s):
Academic department(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:278081
Created by:
Ray, David
Created:
16th November, 2015, 12:01:43
Last modified by:
Ray, David
Last modified:
16th November, 2015, 12:01:43

Can we help?

The library chat service will be available from 11am-3pm Monday to Friday (excluding Bank Holidays). You can also email your enquiry to us.