Serum cholesterol selectively regulates glucocorticoid sensitivity through activation of JNK

    1. Laura C Matthews1
    1. 1Manchester Centre for Nuclear Hormone Research in Disease and Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK
      2Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, CTF Building, Grafton Street, Manchester, M13 9PT, UK
    1. Correspondence should be addressed to L C Matthews or D W Ray; Emails: laura.matthews{at} or david.w.ray{at}


    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.

    • Received in final form 19 August 2014
    • Accepted 25 August 2014
    • Made available online as an Accepted Preprint 26 August 2014
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    1. J Endocrinol 223 155-166
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