Contrasting effects of arachidonic acid and docosahexaenoic acid membrane incorporation into cardiomyocytes on free cholesterol turnover |
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Authors: | Aline Doublet Véronique Robert Benoît Vedie Delphine Rousseau-Ralliard Anne Reboulleau Alain Grynberg Jean-Louis Paul Natalie Fournier |
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Institution: | 1. Univ Paris-Sud, EA 4529, UFR de Pharmacie, 92296 Châtenay-Malabry, France;2. INRA, UMR 1319 MICALIS, Commensal and Probiotics–Host Interactions Laboratory, 78350 Jouy-en-Josas, France;3. AP-HP (Assistance Publique-Hôpitaux de Paris), Hôpital européen Georges Pompidou, Service de Biochimie, 75015 Paris, France;4. INRA, UMR 1198 Biologie du Développement et Reproduction, 78352 Jouy-en-Josas, France;5. ENVA, 94700 Maisons Alfort, France;6. CRNH-IdF, SMBH Université Paris 13, 93000 Bobigny, France |
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Abstract: | The preservation of a constant pool of free cholesterol (FC) is critical to ensure several functions of cardiomyocytes. We investigated the impact of the membrane incorporation of arachidonic acid (C20:4 ω6, AA) or docosahexaenoic acid (C22:6 ω3, DHA) as ω6 or ω3 polyunsaturated fatty acids (PUFAs) on cholesterol homeostasis in primary cultures of neonatal rat cardiac myocytes. We measured significant alterations to the phospholipid FA profiles, which had markedly different ω6/ω3 ratios between the AA and DHA cells (13 vs. 1). The AA cells showed a 2.7-fold lower cholesterol biosynthesis than the DHA cells. Overall, the AA cells showed 2-fold lower FC masses and 2-fold higher cholesteryl ester masses than the DHA cells. The AA cells had a lower FC to phospholipid ratio and higher triglyceride levels than the DHA cells. Moreover, the AA cells showed a 40% decrease in ATP binding cassette transporter A1 (ABCA1)-mediated and a 19% decrease in ABCG1-mediated cholesterol efflux than the DHA cells. The differences in cholesterol efflux pathways induced by AA or DHA incorporation were not caused by variations in ABCs transporter expression and were reduced when ABC transporters were overexpressed by exposure to LXR/RXR agonists. These results show that AA incorporation into cardiomyocyte membranes decreased the FC turnover by markedly decreasing the endogenous cholesterol synthesis and by decreasing the ABCA1- and ABCG1-cholesterol efflux pathways, whereas DHA had the opposite effects. We propose that these observations may partially contribute to the beneficial effects on the heart of a diet containing a high ω3/ω6 PUFA ratio. |
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Keywords: | AA arachidonic acid ABCA1 ATP binding cassette transporter A1 ABCG1 ATP binding cassette transporter G1 apo apolipoprotein CE cholesteryl esters DHA docosahexaenoic acid FA fatty acids FC free cholesterol LXR/RXR liver X receptor/retinoid X receptor MUFA monounsaturated fatty acid PL phospholipids PUFA polyunsaturated fatty acid SFA saturated fatty acid SREBP sterol regulatory element binding proteins TG triglycerides |
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