Intestinal apolipoprotein A-IV gene transcription is controlled by two hormone-responsive elements: a role for hepatic nuclear factor-4 isoforms.
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)-4alpha and gamma. Here, intraduodenal injections in mice and infections of human enterocytic Caco-2/TC7 cells with an adenovirus expressing a dominant-negative form of HNF-4alpha repress the expression of the apoA-IV gene, demonstrating that HNF-4 controls the apoA-IV gene expression in enterocytes. We show that HNF-4alpha and gamma 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.
Archer
Amena
A
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.
Sauvaget
Dominique
D
Chauffeton
Valérie
V
Bouchet
Pierre-Etienne
PE
Chambaz
Jean
J
Pinçon-Raymond
Martine
M
Cardot
Philippe
P
Ribeiro
Agnès
A
Lacasa
Michel
M
D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics*; D018938:Caco-2 Cells; D004742:Enhancer Elements, Genetic / Q000235:genetics; D020895:Enterocytes / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020218:Response Elements / Q000235:genetics*; D014158:Transcription, Genetic
D001054:Apolipoproteins A; D020033:Protein Isoforms; C022205:apolipoprotein A-IV