6533b822fe1ef96bd127ccd5
RESEARCH PRODUCT
Liver X receptor activation promotes polyunsaturated fatty acid synthesis in macrophages : relevance in the context of atherosclerosis
David MassonAmalia TroussonJean Paul Pais De BarrosJean-marc A. LobaccaroMinako IshibashiThomas GautierAlexis VarinMichel NarceVictoria BergasLaurent LagrostCharles ThomasLouise Ménégautsubject
Context (language use)Biologydigestive systemchemistry.chemical_compoundMicearachidonic acidAnimalsHumansFatty acid homeostasisReceptorLiver X receptor[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry Molecular BiologyLiver X Receptorschemistry.chemical_classificationCholesterolFatty acidfood and beveragesArteriesAtherosclerosisOrphan Nuclear ReceptorsmacrophagesBiochemistrychemistryn-3 polyunsaturated fatty acidFatty Acids UnsaturatedArachidonic acidlipids (amino acids peptides and proteins)Cardiology and Cardiovascular MedicineSterol Regulatory Element Binding Protein 1Polyunsaturated fatty acidFoam Cellsliver X receptordescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-05-20 |