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Glucocorticoid receptor-mediated upregulation of human CYP27A1, a potential anti-atherogenic enzyme
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2008 (English)In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1781, no 11-12, 718-723 p.Article in journal (Refereed) Published
Abstract [en]

Sterol 27-hydroxylase (CYP27A1) is required for the hepatic conversion of cholesterol into bile acids and for production of 27-hydroxycholesterol which affects cholesterol homeostasis in several ways. Dexamethasone increases hepatic bile acid biosynthesis and CYP27A1-mediated enzyme activity in HepG2 cells. This study examines the mechanism of the dexamethasone-induced effect on the human CYP27A1 promoter. Dexamethasone treatment of HepG2 cells overexpressed with glucocorticoid receptor alpha (GRalpha) increased the CYP27A1 promoter activity more than four-fold as compared with untreated cells. The GR-antagonist mifepristone almost completely abolished the dexamethasone-induced effect on the promoter activity. Progressive deletion analysis of the CYP27A1 promoter indicated that sequences involved in GR-mediated induction by dexamethasone are present in a region between -1094 and -792. Several putative GRE sites could be found in this region and EMSA experiments revealed that two of these could bind GR. Site-directed mutagenesis of GR-binding sequences in the CYP27A1 promoter identified a GRE at -824/-819 important for GR-mediated regulation of the transcriptional activity. Endogenous and pharmacological glucocorticoids may have a strong impact on several aspects of cholesterol homeostasis and other processes related to CYP27A1-mediated metabolism. The glucocorticoid-mediated induction of human CYP27A1 transcription is of particular interest due to the anti-atherogenic properties ascribed to this enzyme.

Place, publisher, year, edition, pages
2008. Vol. 1781, no 11-12, 718-723 p.
Keyword [en]
Human CYP27A1, 27-Hydroxylation, Dexamethasone, Glucocorticoid receptor, Atherosclerosis, Transcriptional regulation
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-104846DOI: 10.1016/j.bbalip.2008.08.005ISI: 000261675400006PubMedID: 18817892OAI: oai:DiVA.org:uu-104846DiVA: diva2:220182
Available from: 2009-05-29 Created: 2009-05-29 Last updated: 2017-12-13Bibliographically approved

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Norlin, MariaWikvall, Kjell

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