Glucocorticoid receptor-mediated upregulation of human CYP27A1, a potential anti-atherogenic enzyme
2008 (English)In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1388-1918, Vol. 1781, no 11-12, 718-723 p.Article in journal (Refereed) Published
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.
Human CYP27A1, 27-Hydroxylation, Dexamethasone, Glucocorticoid receptor, Atherosclerosis, Transcriptional regulation
IdentifiersURN: urn:nbn:se:uu:diva-104846DOI: 10.1016/j.bbalip.2008.08.005ISI: 000261675400006PubMedID: 18817892OAI: oai:DiVA.org:uu-104846DiVA: diva2:220182