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Hepatocyte Nuclear Factor-4 Regulates the Human Apolipoprotein AV Gene: Identification of a Novel Response Element and Involvement in the Control by Peroxisome Proliferator-Activated Receptor- Coactivator-1, AMP-Activated Protein Kinase, and Mitogen-Activated Protein Kinase Pathway

GlaxoSmithKline (X.P., H.C., J.C.R.), 91951 Les Ulis cedex, France; and Academic Medical Center Liver Center (F.G.S.), 105 BK Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Joan C. Rodríguez, GlaxoSmithKline, 25 avenue du Québec, 91951 Les Ulis cedex, France. E-mail: jcrodrig{at}freesurf.fr.

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.

NURSA Molecule Pages Link:

Nuclear Receptors:   FXRα  |  HNF4α

Coregulators:   PGC-1

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