Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production.
In: ISSN: 0195-668X, 2013
Online
academicJournal
Zugriff:
International audience ; AIMS: Peroxisome proliferator-activated receptor (PPAR)-α is a transcription factor controlling lipid metabolism in liver, heart, muscle, and macrophages. Peroxisome proliferator-activated receptor-α activation increases plasma HDL cholesterol and exerts hypotriglyceridaemic actions via the liver. However, the intestine expresses PPAR-α, produces HDL and chylomicrons, and is exposed to diet-derived PPAR-α ligands. Therefore, we examined the effects of PPAR-α activation on intestinal lipid and lipoprotein metabolism. METHODS AND RESULTS: The impact of PPAR-α activation was evaluated in term of HDL-related gene expression in mice, ex vivo in human jejunal biopsies and in Caco-2/TC7 cells. Apolipoprotein-AI/HDL secretion, cholesterol esterification, and trafficking were also studied in vitro. In parallel to improving plasma lipid profiles and increasing liver and intestinal expression of fatty acid oxidation genes, treatment with the dual PPAR-α/δ ligand GFT505 resulted in a more pronounced increase in plasma HDL compared with fenofibrate in mice. GFT505, but not fenofibrate, increased the expression of HDL production genes such as apolipoprotein-AI and ATP-binding cassette A1 transporter in murine intestines. A similar increase was observed upon PPAR-α activation of human biopsies and Caco-2/TC7 cells. Additionally, HDL secretion by Caco-2/TC7 cells increased. Moreover, PPAR-α activation decreased the cholesterol esterification capacity of Caco-2/TC7 cells, modified cholesterol trafficking, and reduced apolipoprotein-B secretion. CONCLUSION: Peroxisome proliferator-activated receptor-α activation reduces cholesterol esterification, suppresses chylomicron, and increases HDL secretion by enterocytes. These results identify the intestine as a target organ of PPAR-α ligands with entero-hepatic tropism to reduce atherogenic dyslipidaemia.
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Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production.
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Autor/in / Beteiligte Person: | Colin, Sophie ; Briand, Olivier ; Touche, Véronique ; Wouters, Kristiaan ; Baron, Morgane ; Pattou, François ; Hanf, Rémy ; Tailleux, Anne ; Chinetti, Giulia ; Staels, Bart ; Lestavel, Sophie ; Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD) ; Institut Pasteur de Lille ; Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille) ; Service de chirurgie générale et endocrinienne ; Hôpital Claude Huriez Lille ; Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille)-Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille) ; Thérapie cellulaire du diabète ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé ; Genfit ; Entreprise biopharmaceutique GENFIT Loos ; This work was supported by grants from Université Lille 2, Région Nord/Pas-de-Calais, the FEDER and the "Fondation Leducq". |
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Zeitschrift: | ISSN: 0195-668X, 2013 |
Veröffentlichung: | HAL CCSD ; Oxford University Press (OUP), 2013 |
Medientyp: | academicJournal |
DOI: | 10.1093/eurheartj/ehs227 |
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