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Molecular and Cellular Biology, February 2005, p. 1537-1548, Vol. 25, No. 4
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.4.1537-1548.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Insulin-Mediated Down-Regulation of Apolipoprotein A5 Gene Expression through the Phosphatidylinositol 3-Kinase Pathway: Role of Upstream Stimulatory Factor

Maxime Nowak,1 Audrey Helleboid-Chapman,1 Heidelinde Jakel,1 Geneviève Martin,2 Daniel Duran-Sandoval,1 Bart Staels,1 Edward M. Rubin,3 Len A. Pennacchio,3 Marja-Riitta Taskinen,4 Jamila Fruchart-Najib,1* and Jean-Charles Fruchart1

Département d'Athérosclérose, UR 545 INSERM, Institut Pasteur de Lille et Université de Lille II, Lille,1 Genfit SA, Loos, France,2 Genome Sciences Department and Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, California,3 Department of Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland4

Received 8 October 2004/ Accepted 8 November 2004

The apolipoprotein A5 gene (APOA5) has been repeatedly implicated in lowering plasma triglyceride levels. Since several studies have demonstrated that hyperinsulinemia is associated with hypertriglyceridemia, we sought to determine whether APOA5 is regulated by insulin. Here, we show that cell lines and mice treated with insulin down-regulate APOA5 expression in a dose-dependent manner. Furthermore, we found that insulin decreases human APOA5 promoter activity, and subsequent deletion and mutation analyses uncovered a functional E box in the promoter. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that this APOA5 E box binds upstream stimulatory factors (USFs). Moreover, in transfection studies, USF1 stimulates APOA5 promoter activity, and the treatment with insulin reduced the binding of USF1/USF2 to the APOA5 promoter. The inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway abolished insulin's effect on APOA5 gene expression, while the inhibition of the P70 S6 kinase pathway with rapamycin reversed its effect and increased APOA5 gene expression. Using an oligonucleotide precipitation assay for USF from nuclear extracts, we demonstrate that phosphorylated USF1 fails to bind to the APOA5 promoter. Taken together, these data indicate that insulin-mediated APOA5 gene transrepression could involve a phosphorylation of USFs through the PI3K and P70 S6 kinase pathways that modulate their binding to the APOA5 E box and results in APOA5 down-regulation. The effect of exogenous hyperinsulinemia in men showed a decrease in the plasma ApoAV level. These results suggest a potential contribution of the APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia.

* Corresponding author. Mailing address: Parc Eurasanté-Université de Lille 2, 885 Ave. Eugène Avinée, 59120 Loos, France. Phone: 33 3 20 16 40 84. Fax: 33 3 20 16 40 01. E-mail: jfruchart{at}pharma.univ-lille2.fr.

Molecular and Cellular Biology, February 2005, p. 1537-1548, Vol. 25, No. 4
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.4.1537-1548.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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