Eicosapentaenoic acid membrane incorporation impairs ABCA1-dependent cholesterol efflux via a protein kinase A signaling pathway in primary human macrophages |
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| Affiliation: | 2. Laboratoire de Biochimie, AP-HP (Assistance Publique-Hôpitaux de Paris), Hôpital Européen Georges Pompidou, 75015 Paris, France;3. Laboratoire de Biochimie hormonale, AP-HP (Assistance Publique-Hôpitaux de Paris), Hôpital Robert Debré, 75019 Paris, France;4. UMR INRA 1198, Biologie du Développement et Reproduction, Jouy-en-Josas, France;1. Department of Biology, University of Bergen and Hjort Centre for Marine Ecosystem Dynamics, P.O. Box 7803, 5020 Bergen, Norway;2. Institute of Marine Research (IMR) and Hjort Centre for Marine Ecosystem Dynamics, P.O. Box 1870 Nordnes, 5817 Bergen, Norway;3. Centre for Ecological and Evolutionary Synthesis (CEES), Department of Biosciences, University of Oslo, P.O. Box 1066, Blindern, 0316 Oslo, Norway;1. Facultad de Ingeniería y Ciencias Aplicadas, Universidad de los Andes, Monseñor Álvaro del Portillo 12455, Las Condes, Santiago, Chile;2. Departamento de Ingeniería Química y Biotecnología, Universidad de Chile, Casilla 2777, Santiago, Chile;3. Department of Chemistry, Universidad Tecnológica Metropolitana, Las Palmeras 3360, Ñuñoa, Santiago, Chile |
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| Abstract: | A diet rich in n-3/n-6 polyunsaturated fatty acids (PUFAs) is cardioprotective. Dietary PUFAs affect the cellular phospholipids composition, which may influence the function of membrane proteins. We investigated the impact of the membrane incorporation of several PUFAs on ABCA1-mediated cholesterol efflux, a key antiatherogenic pathway. Arachidonic acid (AA) (C20:4 n-6) and docosahexaenoic acid (DHA) (C22:6 n-3) decreased or increased cholesterol efflux from J774 mouse macrophages, respectively, whereas they had no effect on efflux from human monocyte-derived macrophages (HMDM). Importantly, eicosapentaenoic acid (EPA) (C20:5 n-3) induced a dose-dependent reduction of ABCA1 functionality in both cellular models (− 28% for 70 μM of EPA in HMDM), without any alterations in ABCA1 expression. These results show that PUFA membrane incorporation does not have the same consequences on cholesterol efflux from mouse and human macrophages. The EPA-treated HMDM exhibited strong phospholipid composition changes, with high levels of both EPA and its elongation product docosapentaenoic acid (DPA) (C22:5 n-3), which is associated with a decreased level of AA. In HMDM, EPA reduced the ATPase activity of the membrane transporter. Moreover, the activation of adenylate cyclase by forskolin and the inhibition of cAMP phosphodiesterase by isobutylmethylxanthine restored ABCA1 cholesterol efflux in EPA-treated human macrophages. In conclusion, EPA membrane incorporation reduces ABCA1 functionality in mouse macrophages as well as in primary human macrophages and this effect seems to be PKA-dependent in human macrophages. |
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