title: Liver X receptor activation promotes polyunsaturated fatty acid synthesis in macrophages: relevance in the context of atherosclerosis.
abstract: OBJECTIVE
  Liver X receptors (LXRs) modulate cholesterol and fatty acid homeostasis as well as inflammation. This study aims to decipher the role of LXRs in the regulation of polyunsaturated fatty acid (PUFA) synthesis in macrophages in the context of atherosclerosis.
  
  
  RESULTS
  Transcriptomic analysis in human monocytes and macrophages was used to identify putative LXR target genes among enzymes involved in PUFA biosynthesis. In parallel, the consequences of LXR activation or LXR invalidation on PUFA synthesis and distribution were determined. Finally, we investigated the impact of LXR activation on PUFA metabolism in vivo in apolipoprotein E-deficient mice. mRNA levels of acyl-CoA synthase long-chain family member 3, fatty acid desaturases 1 and 2, and fatty acid elongase 5 were significantly increased in human macrophages after LXR agonist treatment, involving both direct and sterol responsive element binding protein-1-dependent mechanisms. Subsequently, pharmacological LXR agonist increased long chain PUFA synthesis and enhanced arachidonic acid content in the phospholipids of human macrophages. Increased fatty acid desaturases 1 and 2 and acyl-CoA synthase long-chain family member 3 mRNA levels as well as increased arachidonic acid to linoleic acid and docosahexaenoic acid to eicosapentaenoic acid ratios were also found in atheroma plaque and peritoneal foam cells from LXR agonist-treated mice. By contrast, murine LXR-deficient macrophages displayed reduced expression of fatty acid elongase 5, acyl-CoA synthase long-chain family member 3 and fatty acid desaturases 1, as well as decreased cellular levels of docosahexaenoic acid and arachidonic acid.
  
  
  CONCLUSIONS
  Our results indicate that LXR activation triggers PUFA synthesis in macrophages, which results in significant alterations in the macrophage lipid composition. Moreover, we demonstrate here that LXR agonist treatment modulates PUFA metabolism in atherosclerotic arteries.
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Alexis
authors.initials: A
authors.lastname: Varin
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Charles
authors.initials: C
authors.lastname: Thomas
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Minako
authors.initials: M
authors.lastname: Ishibashi
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Louise
authors.initials: L
authors.lastname: Ménégaut
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Amalia
authors.initials: A
authors.lastname: Trousson
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Victoria
authors.initials: V
authors.lastname: Bergas
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Jean Paul Pais
authors.initials: JP
authors.lastname: de Barros
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Michel
authors.initials: M
authors.lastname: Narce
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Jean Marc A
authors.initials: JM
authors.lastname: Lobaccaro
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Lagrost
authors.affiliation: From the Centre de Recherche INSERM-UMR866, Université de Bourgogne, Dijon, France (A.V., C.T., M.I., L.M., T.G., V.B., J.P.P.d.B., M.N., L.L., D.M.); Centre Hospitalier Universitaire Dijon, Dijon, France (L.M., L.L., D.M.); Clermont Université, Université Blaise Pascal (A.T., J.M.A.L.) and Inserm, UMR 1103 (A.T., J.M.A.L.), GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France (A.T., J.M.A.L.); and Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 6293, Aubière, France (A.T., J.M.A.L.). david.masson@chu-dijon.fr.
authors.forename: David
authors.initials: D
authors.lastname: Masson
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001158:Arteries / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis*; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D005231:Fatty Acids, Unsaturated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D016718:Arachidonic Acid
keywords: arachidonic acid; liver X receptor; macrophages; n-3 polyunsaturated fatty acid