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.

L iver X receptor-α (LXRα) and LXRβ (Nr1h3 and Nr1h2, respectively) are oxysterol-activated nuclear receptors that regulate the expression of genes involved in different pathways, such as cholesterol and fatty acid (FA) metabolism or inflammation.1 LXRs are attractive targets in the field of atherosclerosis because LXR activation improves cholesterol homeostasis and promotes cholesterol removal from macrophages through the coordinate regulation of apolipoprotein E and the cholesterol transporters ATP-binding cassette transporter A1 and and ATP-binding cassette transporter G1. LXR also stimulates lipogenesis and the production of monounsaturated FAs through induction of prolipogenic genes, including sterol regulatory element-binding protein 1c, FA synthase, and stearoyl CoA desaturase.1 In addition, a specific role for LXR in cellular phospholipid (PL) metabolism was recently described because LXR activation was shown to reduce the biosynthesis of phosphatidylethanolamines by inhibiting the CTP:phosphoethanolamine cytidylyltransferase, an enzyme involved in the Kennedy pathway. 2 Besides cholesterol and FA metabolism, a major function for LXR in macrophages is the control of innate immunity. Treatment of murine macrophages with synthetic LXR agonists attenuates the inflammatory response to lipopolysaccharide (LPS) 3 and it has been demonstrated that LXR ligands can induce the sumoylation of LXR, which subsequently forms complexes with nuclear receptor corepressor 1 and SMRT that inhibit NF-κB-mediated and AP-1-mediated inflammatory response. 4,5 In contrast to mouse macrophages, treatment of human macrophages with © 2013 American Heart Association, Inc. Objective-Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that are highly expressed in macrophages and regulate lipid homeostasis and inflammation. Among putative LXR target genes, lysophosphatidylcholine acyltransferase 3 (LPCAT3) involved in the Lands cycle controls the fatty acid composition at the sn-2 position of glycerophospholipids and, therefore, the availability of fatty acids, such as arachidonic acid (AA), used for eicosanoid synthesis. The aim of our study was to determine whether LXRs could regulate the Lands cycle in human macrophages, to assess the consequences in terms of lipid composition and inflammatory response, and to work out the relative contribution of LPCAT3 to the observed changes. Approach and Results-Transcriptomic analysis revealed that LPCAT3 was upregulated by LXR agonists in human macrophages. Accordingly, LXR stimulation significantly increased lysophospholipid acyltransferase activity catalyzed by LPCAT3. Lipidomic analysis demonstrated that LXR activation increased the AA content in the polar lipid fraction, specifically in phosphatidylcholines. The LXR-mediated effects on AA distribution were abolished by LPCAT3 silencing, and a redistribution of AA toward the neutral lipid fraction was observed in this context. Finally, we observed that preconditioning of human macrophages by LXR agonist treatment increased...