A high plasma concentration of lipoprotein(a) [Lp(a)] confers an increased risk for the development of coronary heart disease. Hormones, such as oestrogen, are some of the few compounds known to reduce plasma Lp(a) levels. A putative enhancer region, located at the DHII DNase I hypersensitive site approx. 28kb upstream of the apolipoprotein(a) [apo(a)] gene, contains a number of sequences similar to the binding half-sites for nuclear hormone receptors, such as the oestrogen receptor and the peroxisome proliferator-activated receptor (PPAR). The 180bp core DHII enhancer increased the activity of the apo(a) promoter by over 7-fold in reporter-gene assays in HepG2 cells in vitro. Almost 60% of this increase was lost in the presence of co-transfected oestrogen receptor and oestrogen. In contrast, co-transfection with PPARα increased the effect of the DHII enhancer on apo(a) transcriptional activity by approx. 70% and could overcome the inhibitory effect of the oestrogen receptor on apo(a) transcription. Gel mobility-shift assays showed that oestrogen receptor protein bound to one half of a sequence corresponding to a predicted oestrogen receptor response element. PPARα also bound to this site and competed with oestrogen receptors for binding. In addition, PPARα bound to a separate site that comprised part of a direct repeat of nuclear hormone receptor half-sites. The results suggest that nuclear hormones affect plasma Lp(a) concentrations by binding to the sequences within the DHII enhancer, thereby altering the amount by which the enhancer increases the transcription of the apo(a) gene.
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August 2002
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Research Article|
August 15 2002
Interaction of oestrogen and peroxisome proliferator-activated receptors with apolipoprotein(a) gene enhancers
Loretto H. PUCKEY;
Loretto H. PUCKEY
Lipoprotein Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital, DuCane Road, London W12 ONN, U.K.
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Brian L. KNIGHT
Brian L. KNIGHT
1
Lipoprotein Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital, DuCane Road, London W12 ONN, U.K.
1To whom correspondence should be addressed (e-mail brian.knight@csc.mrc.ac.uk).
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Publisher: Portland Press Ltd
Received:
February 19 2002
Revision Received:
May 09 2002
Accepted:
May 22 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (1): 157–163.
Article history
Received:
February 19 2002
Revision Received:
May 09 2002
Accepted:
May 22 2002
Citation
Loretto H. PUCKEY, Brian L. KNIGHT; Interaction of oestrogen and peroxisome proliferator-activated receptors with apolipoprotein(a) gene enhancers. Biochem J 15 August 2002; 366 (1): 157–163. doi: https://doi.org/10.1042/bj20020293
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