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Title: The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element
Author: Prieur, X.
Coste, H.
Rodríguez Rubio, Joan Carles
Keywords: Apoproteïnes
Transcripció genètica
Genetic transcription
Issue Date: 22-Apr-2003
Publisher: American Society for Biochemistry and Molecular Biology
Abstract: The newly identified apolipoprotein AV (apoAV) gene is a key player in determining plasma triglyceride concentrations. Because hypertriglyceridemia is a major independent risk factor in coronary artery disease, the understanding of the regulation of the expression of this gene is of considerable importance. We presently characterize the structure, the transcription start site, and the promoter of the human apoAV gene. Since the peroxisome proliferator-activated receptor- (PPAR ) and the farnesoid X-activated receptor (FXR) have been shown to modulate the expression of genes involved in triglyceride metabolism, we evaluated the potential role of these nuclear receptors in the regulation of apoAV transcription. Bile acids and FXR induced the apoAV gene promoter activity. 5 -Deletion, mutagenesis, and gel shift analysis identified a heretofore unknown element at positions 103/ 84 consisting of an inverted repeat of two consensus receptor-binding hexads separated by 8 nucleotides (IR8), which was required for the response to bile acid-activated FXR. The isolated IR8 element conferred FXR responsiveness on a heterologous promoter. On the other hand, in apoAV-expressing human hepatic Hep3B cells, transfection of PPAR specifically enhanced apoAV promoter activity. By deletion, site-directed mutagenesis, and binding analysis, a PPAR response element located 271 bp upstream of the transcription start site was identified. Finally, treatment with a specific PPAR activator led to a significant induction of apoAV mRNA expression in hepatocytes. The identification of apoAV as a PPAR target gene has major implications with respect to mechanisms whereby pharmacological PPAR agonists may exert their beneficial hypotriglyceridemic actions.
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It is part of: Journal of Biological Chemistry, 2003, vol. 278, num. 28, p. 25468-25480
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ISSN: 0021-9258
Appears in Collections:Articles publicats en revistes (Bioquímica i Fisiologia)

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