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J. Biol. Chem., Vol. 280, Issue 7, 5406-5413, February 18, 2005

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HNF-4-dependent Induction of Apolipoprotein A-IV Gene Transcription by an Apical Supply of Lipid Micelles in Intestinal Cells^*

Véronique Carrière, Romain Vidal, Kristell Lazou, Michel Lacasa, François Delers, Agnès Ribeiro, Monique Rousset, Jean Chambaz, and Jean Marc Lacorte

From the INSERM UMR505, Paris F-75006, France and Université Pierre et Marie Curie, Paris F-75006, France

Apolipoprotein (apo) A-IV, a component of triglyceride-rich lipoproteins secreted by the small intestine, has been shown to play an important role in the control of lipid homeostasis. Numerous studies have described the induction of apoA-IV gene expression by lipids, but the molecular mechanisms involved in this process remain unknown. In this study, we have demonstrated that a lipid bolus induced transcription of the apoA-IV gene in transgenic mice and that the regulatory region of the apoA-IV gene, composed of the apoC-III enhancer and the apoA-IV promoter (eC3-A4), was responsible for this induction. In enterocyte Caco-2/TC7 cells, a permanent supply of lipids at the basal pole induced expression of the apoA-IV gene both at the transcriptional level and through mRNA stabilization. ApoA-IV gene transcription and protein secretion were further induced by an apical supply of complex lipid micelles mimicking the composition of duodenal micelles, and this effect was not reproduced by apical delivery of different combinations of micelle components. Only induction of the apoA-IV gene by lipid micelles involved the participation of hepatic nuclear factor (HNF)-4, as demonstrated using a dominant negative form of this transcription factor. Accordingly, lipid micelles increased the DNA binding activity of HNF-4 on the eC3-A4 region. These results emphasize the importance of physiological delivery of dietary lipids on apoA-IV gene expression and the implication of HNF-4 in this regulation.

Received for publication, July 15, 2004 , and in revised form, November 29, 2004.

^* This work was supported in part by ATC Nutrition INSERM Grant ASE02129DSA. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a grant from l'Agence pour la Recherche et l'Information en Fruits et Légumes frais (APRIFEL).

To whom correspondence should be addressed: UMR505 INSERM/UPMC, Centre de Recherches Biomédicales des Cordeliers, 15 rue de l'Ecole de Médecine, 75006 Paris, France. Tel.: 33-01-42-34-69-34; Fax: 33-01-43-25-16-15; E-mail: Veronique.Carriere-u505{at}bhdc.jussieu.fr.

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