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Title: | Hepatocyte nuclear factor-4 alpha regulates the human apolipoprotein AV gene: Identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, AMP-activated protein kinase, and mitogen-activated protein kinase pathway |
Author: | Prieur, Xavier Schaap, Frank G. Coste, Hervé Rodríguez Rubio, Joan Carles |
Keywords: | Lipoproteïnes Genètica Receptors nuclears (Bioquímica) Factors de transcripció Àcids nucleics Lipoproteins Genetics Nuclear receptors (Biochemistry) Transcription factors Nucleic acids |
Issue Date: | 1-Dec-2005 |
Publisher: | Endocrine Society |
Abstract: | The recently discovered apolipoprotein AV (apoAV) gene has been reported to be a key player in modulating plasma triglyceride levels. Here we identify the hepatocyte nuclear factor-4 (HNF-4 ) as a novel regulator of human apoAV gene. Inhibition of HNF-4 expression by small interfering RNA resulted in down-regulation of apoAV. Deletion, mutagenesis, and binding assays revealed that HNF-4 directly regulates human apoAV promoter through DR1 [a direct repeat separated by one nucleotide (nt)], and via a novel element for HNF-4 consisting of an inverted repeat separated by 8 nt (IR8). In addition, we show that the coactivator peroxisome proliferator-activated receptor- coactivator-1 was capable of stimulating the HNF-4 -dependent transactivation of apoAV promoter. Furthermore, analyses in human hepatic cells demonstrated that AMP-activated protein kinase (AMPK) and the MAPK signaling pathway regulate human apoAV expression and suggested that this regulation may be mediated, at least in part, by changes in HNF-4 . Intriguingly, EMSAs and mice with a liver-specific disruption of the HNF-4 gene revealed a species-distinct regulation of apoAV by HNF-4 , which resembles that of a subset of HNF-4 target genes. Taken together, our data provide new insights into the binding properties and the modulation of HNF-4 and underscore the role of HNF-4 in regulating triglyceride metabolism. |
Note: | Reproducció del document publicat a: http://dx.doi.org/10.1210/me.2005-0048 |
It is part of: | Molecular Endocrinology, 2005, vol. 19, num. 12, p. 3107-3125 |
URI: | http://hdl.handle.net/2445/48746 |
Related resource: | http://dx.doi.org/10.1210/me.2005-0048 |
ISSN: | 0888-8809 |
Appears in Collections: | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) |
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