Research paper Fibrate treatment induced quantitative and qualitative HDL changes associated with an increase of SR-BI cholesterol efflux capacities in rabbits Natalie Fournier a, b, * , Véronique Tuloup-Minguez a , Marie-Luce Pourci a, c , Patrice Thérond c , Jean-Christophe Jullian d , Frank Wien e , Michel Leroy f , Jean Dallongeville g , Jean-Louis Paul a, b , Arnaud Leroy a, * ,1 a Univ Paris-Sud, EA 4529, UFR de Pharmacie, 92296 Châtenay-Malabry, France b AP-HP (Assistance Publique-Hôpitaux de Paris), Hôpital Européen Georges Pompidou, Service de Biochimie, 75015 Paris, France c AP-HP (Assistance Publique-Hôpitaux de Paris), Hôpital Bicêtre, Service de Biochimie, 94275 Le Kremlin-Bicêtre, France d BioCIS CNRS, UMR 8076, UFR de Pharmacie, 92296 Châtenay-Malabry, France e DISCO Synchrotron Soleil, l’Orme des Merisiers, Saint Aubin BP 48, 91192 Gif sur Yvette, France f INSTRULABO, 92340 Bourg-la-Reine, France g INSERM, U744, Institut Pasteur de Lille, 59019 Lille, France article info Article history: Received 23 October 2012 Accepted 1 February 2013 Available online 11 February 2013 Keywords: Fenofibrate HDL structure LCAT Fatty acid profiles and phospholipid species SR-BI cholesterol efflux abstract Fibrates are widely used as lipid lowering drugs acting as peroxisome proliferator-activated receptors a (PPARa) agonists and modulating the expression of several genes involved in lipid and lipoprotein metabolism. Much less is known on the effect of fibrates in HDL structure and composition. Therefore, we examined whether fenofibrate induces quantitative and/or qualitative modifications in HDL metabolism in the rabbit, an animal that, contrary to rodents and similar to humans, is less sensitive to peroxisome proliferators. We first demonstrated that 3-week treatment with fenofibrate (250 mg/kg/day) induced an important increase in serum apolipoprotein A-I, HDL-cholesterol and HDL-phospholipids concentrations and a relative enrichment in HDL cholesteryl ester content. Moreover, the fatty acid profiles from fenofibrate-treated rabbits displayed a dramatic increase in the serum or HDL C18:3 u6 to C18:2 u6 ratio suggesting higher D6 desaturase activity. In addition, HDL from fenofibrate-treated animals exhibited higher relative proportions of sphingomyelin, phosphatidylinositol and phosphatidylethanolamine. We then reported that fenofibrate induced major changes in the physical characteristics of HDL, mainly a higher size and a faster mobility on agarose gel electrophoresis. Finally, serum or HDL from treated rabbits exhibited higher capacity to promote cholesterol efflux from Scavenger receptor class B type I (SR-BI)-rich Fu5AH cells compared to controls. Our findings demonstrate that fenofibrate has beneficial effects in rabbits by increasing the mass of the circulating HDL pool and by modifying their composition transforming them as better acceptors of cellular cholesterol through SR-BI pathway. These effects of fenofibrate might contribute to its benefits on the prevention and treatment of atherosclerosis. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction Fibrates are normolipidemic compounds that decrease tri- glycerides (TG) and increase HDL levels in humans [1]. Fibrates are drugs indicated for the treatment of hypertriglyceridemia, mixed dyslipidemia, and hypoalphalipoproteinemia, lipid abnormalities commonly observed in patients at high risk of cardiovascular dis- ease, including type 2 diabetes and/or metabolic syndrome [2,3]. Their effects on lipids are attributed to the variations of the expression of several genes involved in the lipoprotein metabolism in the liver [1,4]. If fibrates decrease plasma TG in both humans and rodents, these drugs exert species-specific effects on HDL [5]. Indeed, fibrates increase plasma HDL in humans by inducing both human apolipoprotein (apo) A-I and apo A-II gene expression [6] whereas fibrates decrease plasma HDL in rats by inhibiting liver apo A-I and apo A-II gene expression [7] and have no impact on apo-AI mRNA synthesis in wild rabbits [8]. * Corresponding authors. Univ Paris-Sud, EA 4529, UFR de Pharmacie, 5 rue JB Clément, 92296 Châtenay-Malabry, France. Tel.: þ33 1 46 83 57 23; fax: þ33 1 46 83 53 71. E-mail addresses: natalie_fournier@yahoo.fr (N. Fournier), leroy.arnau@ wanadoo.fr, arnaud.leroy@u-psud.fr (A. Leroy). 1 Tel.: þ33 1 46 83 57 19. Contents lists available at SciVerse ScienceDirect Biochimie journal homepage: www.elsevier.com/locate/biochi 0300-9084/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.biochi.2013.02.001 Biochimie 95 (2013) 1278e1287