{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:19:56Z","timestamp":1784557196646,"version":"3.55.0"},"reference-count":39,"publisher":"Bioscientifica","issue":"2","license":[{"start":{"date-parts":[[2014,8,26]],"date-time":"2014-08-26T00:00:00Z","timestamp":1409011200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/deed.en_GB"}],"content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,11]]},"abstract":"<jats:p>\n                    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-\u03b2-cyclodextrin or inhibition of cellular cholesterol synthesis with simvastatin potentiated the Gc response. To explore the effect\n                    <jats:italic>in vivo<\/jats:italic>\n                    we used\n                    <jats:italic>ApoE<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, a model of hypercholesterolaemia. Consistent with our\n                    <jats:italic>in vitro<\/jats:italic>\n                    studies, we find no impact of elevated cholesterol on the expression of GR, or on the hypothalamic\u2013pituitary\u2013adrenal axis, measured by dexamethasone suppression test. Instead we find selective Gc resistance on some hepatic target genes in\n                    <jats:italic>ApoE<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Therefore, we have discovered an unexpected role for cholesterol as a selective modulator of Gc action\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Taken together these findings reveal a new environmental constraint on Gc action with relevance to both inflammation and cancer.\n                  <\/jats:p>","DOI":"10.1530\/joe-14-0456","type":"journal-article","created":{"date-parts":[[2014,8,28]],"date-time":"2014-08-28T14:33:50Z","timestamp":1409236430000},"page":"155-166","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":10,"title":["Serum cholesterol selectively regulates glucocorticoid sensitivity through activation of JNK"],"prefix":"10.1530","volume":"223","author":[{"given":"Nan","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Caratti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise M","family":"Ince","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toryn 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