title: Serum cholesterol selectively regulates glucocorticoid sensitivity through activation of JNK.
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.
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Institute of Human DevelopmentFaculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UKInstitute of Cardiovascular SciencesFaculty of Medical and Human Sciences, University of Manchester, CTF Building, Grafton Street, Manchester, M13 9PT, UK.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Institute of Human DevelopmentFaculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UKInstitute of Cardiovascular SciencesFaculty of Medical and Human Sciences, University of Manchester, CTF Building, Grafton Street, Manchester, M13 9PT, UK.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Caratti
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Institute of Human DevelopmentFaculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UKInstitute of Cardiovascular SciencesFaculty of Medical and Human Sciences, University of Manchester, CTF Building, Grafton Street, Manchester, M13 9PT, UK.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Ince
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Institute of Human DevelopmentFaculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UKInstitute of Cardiovascular SciencesFaculty of Medical and Human Sciences, University of Manchester, CTF Building, Grafton Street, Manchester, M13 9PT, UK.
authors.forename: Toryn M
authors.initials: TM
authors.lastname: Poolman
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Institute of Human DevelopmentFaculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UKInstitute of Cardiovascular SciencesFaculty of Medical and Human Sciences, University of Manchester, CTF Building, Grafton Street, Manchester, M13 9PT, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Trebble
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Institute of Human DevelopmentFaculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UKInstitute of Cardiovascular SciencesFaculty of Medical and Human Sciences, University of Manchester, CTF Building, Grafton Street, Manchester, M13 9PT, UK.
authors.forename: Cathy M
authors.initials: CM
authors.lastname: Holt
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Institute of Human DevelopmentFaculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UKInstitute of Cardiovascular SciencesFaculty of Medical and Human Sciences, University of Manchester, CTF Building, Grafton Street, Manchester, M13 9PT, UK laura.matthews@manchester.ac.uk david.w.ray@manchester.ac.uk.
authors.forename: David W
authors.initials: DW
authors.lastname: Ray
authors.affiliation: Manchester Centre for Nuclear Hormone Research in Disease and Institute of Human DevelopmentFaculty of Medical and Human Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UKInstitute of Cardiovascular SciencesFaculty of Medical and Human Sciences, University of Manchester, CTF Building, Grafton Street, Manchester, M13 9PT, UK laura.matthews@manchester.ac.uk david.w.ray@manchester.ac.uk.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Matthews
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D002784:Cholesterol / Q000097:blood*; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008661:Metabolism, Inborn Errors / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011965:Receptors, Glucocorticoid / Q000172:deficiency / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D002784:Cholesterol; D048031:JNK Mitogen-Activated Protein Kinases
keywords: cholesterol; glucocorticoid receptor; inflammatory disease; signal transduction; transcription factors