title: HNF-4-dependent induction of apolipoprotein A-IV gene transcription by an apical supply of lipid micelles in intestinal cells.
abstract: 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.
authors.affiliation: UMR505 INSERM/UPMC, Centre de Recherches Biomédicales des Cordeliers, 15 rue de l'Ecole de Médecine, 75006 Paris F-75006, France. Veronique.Carriere-u505@bhdc.jussieu.fr
authors.forename: Véronique
authors.initials: V
authors.lastname: Carrière
authors.forename: Romain
authors.initials: R
authors.lastname: Vidal
authors.forename: Kristell
authors.initials: K
authors.lastname: Lazou
authors.forename: Michel
authors.initials: M
authors.lastname: Lacasa
authors.forename: François
authors.initials: F
authors.lastname: Delers
authors.forename: Agnès
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Monique
authors.initials: M
authors.lastname: Rousset
authors.forename: Jean
authors.initials: J
authors.lastname: Chambaz
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Lacorte
mesh_terms: D001054:Apolipoproteins A / Q000235:genetics*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D016764:Cell Polarity; D003470:Culture Media / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D008055:Lipids / Q000008:administration & dosage / Q000494:pharmacology*; D008823:Micelles; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001054:Apolipoproteins A; D003470:Culture Media; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D051557:Hepatocyte Nuclear Factor 4; D008055:Lipids; D008823:Micelles; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; C022205:apolipoprotein A-IV