Alexis Varin1, Charles Thomas1, Minako Ishibashi1, Louise Ménégaut1, Thomas Gautier1, Amalia Trousson1, Victoria Bergas1, Jean Paul Pais de Barros1, Michel Narce1, Jean Marc A Lobaccaro1, Laurent Lagrost1, David Masson2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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. APPROACH AND 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-deficientmice. 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, murineLXR-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: Xiaowei Sun; Mary E Haas; Ji Miao; Abhiruchi Mehta; Mark J Graham; Rosanne M Crooke; Jean-Paul Pais de Barros; Jian-Guo Wang; Masanori Aikawa; David Masson; Sudha B Biddinger Journal: J Biol Chem Date: 2015-10-28 Impact factor: 5.157
Authors: Andreas Körner; Enchen Zhou; Christoph Müller; Yassene Mohammed; Sandra Herceg; Franz Bracher; Patrick C N Rensen; Yanan Wang; Valbona Mirakaj; Martin Giera Journal: Proc Natl Acad Sci U S A Date: 2019-09-23 Impact factor: 11.205
Authors: Sophie R Liebergall; Jerry Angdisen; Shun Hang Chan; YingJu Chang; Timothy F Osborne; Alexander F Koeppel; Stephen D Turner; Ira G Schulman Journal: Mol Cell Biol Date: 2020-01-03 Impact factor: 4.272