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Hormonal regulation of the human sterol 27-hydroxylase gene (CYP27A1)
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.
2003 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 372, no Part 2, 529-534 p.Article in journal (Refereed) Published
Abstract [en]

The nucleotide sequence data reported in this paper will appear in EMBL Nucleotide Sequence Database under the accession number AJ 544720. The mitochondrial sterol 27-hydroxylase (CYP27A1) is a multifunctional cytochrome P450 enzyme that catalyses important hydroxylations in the biosynthesis of bile acids and bioactivation of vitamin D(3). Previous results [Babiker, Andersson, Lund, Xiu, Deeb, Reshef, Leitersdorf, Diczfalusy and Bj örkhem (1997) J. Biol. Chem. 272, 26253-26261] suggest that CYP27A1 plays an important role in cholesterol homoeostasis and affects atherogenesis. In the present study, the regulation of the human CYP27A1 gene by growth hormone (GH), insulin-like growth factor-1 (IGF-1), dexamethasone, thyroid hormones and PMA was studied. HepG2 cells were transfected transiently with luciferase reporter gene constructs containing DNA fragments flanking the 5'-region of the human CYP27A1 gene. GH, IGF-1 and dexamethasone increased the promoter activity by 2-3-fold, whereas thyroxine (T(4)) and PMA repressed the activity significantly when measured with luciferase activity expressed in the cells. The endogenous CYP27A1 enzyme activity in the cells was stimulated by GH, IGF-1 and dexamethasone, whereas T(4) and PMA inhibited the activity. Experiments with progressive deletion/luciferase reporter gene constructs indicated that the response elements for GH may be localized in a region upstream to position -1094 bp. The putative response elements for dexamethasone were mapped to positions between -792 and -1095 bp. The -451 bp fragment of the human CYP27A1 gene was found to confer the activation by IGF-1, and the inhibition by T(4) and PMA. Results of the present study suggest that CYP27A1 is regulated in human cells by hormones and signal-transduction pathways.

Place, publisher, year, edition, pages
2003. Vol. 372, no Part 2, 529-534 p.
Keyword [en]
bile acid biosynthesis, cholesterol homoeostasis, growth hormone, PMA, thyroid hormone
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-95809DOI: 10.1042/BJ20021651ISI: 000183625800025PubMedID: 12597773OAI: oai:DiVA.org:uu-95809DiVA: diva2:170154
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2011-03-07Bibliographically approved
In thesis
1. Hormonal Regulation of the Human CYP27A1 and CYP7B1 Genes
Open this publication in new window or tab >>Hormonal Regulation of the Human CYP27A1 and CYP7B1 Genes
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

CYP27A1 and CYP7B1 are widely expressed in various human tissues and are two key enzymes involved in the pathways for conversion of cholesterol to bile acids. Also, CYP27A1 is involved in bioactivation of vitamin D3 and CYP7B1 plays a role in 7alpha-hydroxylation of dehydroepiandrosterone and other steroids. Both enzymes have been reported to be relevant to prostate cell proliferation. The current study examines the hormonal regulation of CYP27A1 and CYP7B1.

CYP7B1 was shown to be regulated by estrogens and androgens in human embryonic kidney HEK293 and prostate cancer LNCaP cells. Quantitation of CYP7B1 mRNA in adult and fetal human tissues showed markedly higher CYP7B1 mRNA levels in fetal tissues compared with the corresponding adult ones, except in the liver. This indicates a tissue-specific, developmental regulation of CYP7B1 and suggests an important function for this enzyme in fetal life. CYP7B1 regulation by estrogens may be of importance in fetal development and in other processes where CYP7B1 is involved, including cholesterol homeostasis, cellular proliferation, and CNS function. The regulation of CYP7B1 by sex hormones also suggests an important role for CYP7B1 in balancing prostate hormone levels in human cells.

Results show that CYP27A1 can be regulated by dexamethasone, growth hormone, IGF-1, PMA, estrogens and androgens in liver-derived HepG2 cells. Dexamethasone, growth hormone and IGF-1 stimulated the promoter and endogenous activity of CYP27A1, whereas thyroid hormones and PMA inhibited CYP27A1. The regulatory effects of estrogens and androgens are different depending on the cell types. Thus, the results imply that human CYP27A1 gene is a target for estrogens and androgens, and the expression of CYP27A1 may be affected by endogenous sex hormones and pharmacological compounds with estrogenic or androgenic effects.

The mechanism for the dexamethasone-induced effect on the human CYP27A1 promoter was examined. A GRE was identified important for GR-mediated regulation of CYP27A1 transcriptional activity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 54 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 56
Pharmaceutical biochemistry, CYP27A1, CYP7B1, cholesterol, estrogen, androgen, prostate, glucocorticoid receptor, fetal development, Farmaceutisk biokemi
urn:nbn:se:uu:diva-7837 (URN)978-91-554-6876-7 (ISBN)
Public defence
2007-05-22, C2:301, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2007-04-27 Created: 2007-04-27Bibliographically approved

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