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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
Receptors nuclears (Bioquímica)
Factors de transcripció
Àcids nucleics
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:
It is part of: Molecular Endocrinology, 2005, vol. 19, num. 12, p. 3107-3125
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ISSN: 0888-8809
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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