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Titolo:
The effect of peroxisome-proliferator-activated receptor-alpha on the activity of the cholesterol 7 alpha-hydroxylase gene
Autore:
Patel, DD; Knight, BL; Soutar, AK; Gibbons, GF; Wade, DP;
Indirizzi:
Hammersmith Hosp, Ctr Clin Sci, MRC, Lipoprot Grp, London W12 0NN, EnglandHammersmith Hosp London England W12 0NN rot Grp, London W12 0NN, England Radcliffe Infirm, Nuffield Dept Clin Med, Metab Res Lab, Oxford OX2 6HE, England Radcliffe Infirm Oxford England OX2 6HE Res Lab, Oxford OX2 6HE, England
Titolo Testata:
BIOCHEMICAL JOURNAL
, volume: 351, anno: 2000,
parte:, 3
pagine: 747 - 753
SICI:
0264-6021(20001101)351:<747:TEOPRO>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
DENSITY-LIPOPROTEIN CHOLESTEROL; NUCLEAR RECEPTOR; MESSENGER-RNA; BILE-ACID; TRANSCRIPTIONAL ACTIVITY; HORMONAL-REGULATION; RAT; PROMOTER; EXPRESSION; DISRUPTION;
Keywords:
diurnal rhythm; gene promoter; PPAR alpha-null mice; transcription;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Knight, BL Hammersmith Hosp, Ctr Clin Sci, MRC, Lipoprot Grp, DuCane Rd, London W12 0NN, England Hammersmith Hosp DuCane Rd London England W12 0NN 0NN, England
Citazione:
D.D. Patel et al., "The effect of peroxisome-proliferator-activated receptor-alpha on the activity of the cholesterol 7 alpha-hydroxylase gene", BIOCHEM J, 351, 2000, pp. 747-753

Abstract

Cholesterol 7 alpha -hydroxylase (Cyp7a1) plays a central role in the regulation of bile acid and cholesterol metabolism, and transcription of the gene is controlled by bile acids and hormones acting through a complex interaction with a number of potential steroid-hormone-binding sites. Transcriptional activity of the human CYP7A1 gene promoter transfected into HepG2 cells was decreased in a concentration-dependent manner by co-transfection withan expression vector for peroxisome-proliferator-activated receptor-alpha (PPAR alpha). This effect was augmented by 9-cis-retinoic acid receptor-alpha (RXR alpha) and activators of PPAR alpha to give a maximum inhibition ofapprox. 80 %. The region responsible for this inhibition contained a site known to bind hepatocyte nuclear factor 3 (HNF4), and mutation of this sitegreatly decreased the effect. Co-expression of HNF4 increased promoter activity and decreased the effect of PPAR alpha. Gel-mobility-shift assays failed to detect any binding of PPAR alpha /RXR alpha dimers to any regions ofthe promoter containing potential binding sites. Also the hepatic abundance of Cyp7a1 mRNA in mice in which the PPAR alpha gene was disrupted was thesame as in normal mice, both during the dark phase, when the animals were feeding, and during the light phase, when mRNA abundance was greatly increased. Cholesterol feeding produced the same increase in hepatic Cyp7a1 mRNA abundance in PPAR alpha -null animals as in normals. It is concluded that, whereas PPAR alpha can affect CYP7A1 gene transcription in vitro through anindirect action, probably by competing for cofactors, this is unlikely to be a major influence on Cyp7a1 activity under normal physiological conditions.

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Documento generato il 04/12/20 alle ore 22:34:05