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Intestinal Apolipoprotein A-IV Gene Transcription Is Controlled by Two Hormone-Responsive Elements: A Role for Hepatic Nuclear Factor-4 Isoforms

Unité Mixte de Recherche 505, Institut National de la Santé et de la Recherche Médicale-Université Pierre & Marie Curie, 75006 Paris, France

Address all correspondence and requests for reprints to: Agnès Ribeiro, Unité Mixte de Recherche 505 Institut National de la Santé et de la Recherche Médicale-Université Pierre & Marie Curie, 15 rue de l’Ecole de Médecine, 75006 Paris, France. E-mail: agnes.ribeiro-pillet-u505{at}bhdc.jussieu.fr.

In the small intestine, the expression of the apolipoprotein (apo) C-III and A-IV genes is restricted to the enterocytes of the villi. We have previously shown that, in transgenic mice, specific expression of the human apo C-III requires a hormone-responsive element (HRE) located in the distal region of the human apoA-IV promoter. This HRE binds the hepatic nuclear factors (HNF)-4 and . Here, intraduodenal injections in mice and infections of human enterocytic Caco-2/TC7 cells with an adenovirus expressing a dominant-negative form of HNF-4 repress the expression of the apoA-IV gene, demonstrating that HNF-4 controls the apoA-IV gene expression in enterocytes. We show that HNF-4 and functionally interact with a second HRE present in the proximal region of the human apoA-IV promoter. New sets of transgenic mice expressing mutated forms of the promoter, combined with the human apo C-III enhancer, demonstrate that, whereas a single HRE is sufficient to reproduce the physiological cephalo-caudal gradient of apoA-IV gene expression, both HREs are required for expression that is restricted to villi. The combination of multiple HREs may specifically recruit regulatory complexes associating HNF-4 and either coactivators in villi or corepressors in crypts.

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Nuclear Receptors:   HNF4α  |  HNF4γ

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