Liver X Receptor Activation Promotes Polyunsaturated Fatty Acid Synthesis in Macrophages

Abstract

L iver X receptors (LXRs) α and β (NR1H3 and NR1H2, respectively) are nuclear receptors activated by oxidized derivatives of cholesterol and by intermediates of the cholesterol synthesis pathway. 1,2 LXRs are involved in the regulation of cholesterol homeostasis, in the control of inflammation and the innate immune response. 3,4 Notably, LXR activation stimulates the reverse cholesterol transport pathway through the coordinated activation of cellular cholesterol efflux, plasma cholesterol transport, and finally hepatic and intestinal cholesterol excretion. Besides regulating cholesterol homeostasis, LXRs also play an important role in fatty acid metabolism because several genes of the fatty acid biosynthesis pathway such as acetyl-CoA carboxylase, fatty acid synthase (FASN), and steroyl-CoA desaturase (SCD1) have been shown as direct LXR targets. 5-8 Key lipogenic transcription factors including the sterol responsive element binding protein 1c (SREBP1), carbohydrate-response element-binding protein, and peroxi-some proliferator activated receptor γ are also directly regulated by LXR. 9-11 Accordingly, pharmacological activation of LXRs results in a marked stimulation of lipogenesis in vivo, particularly in the liver. As a consequence, the administration of a synthetic LXR agonist such as T0901317 in mice induces 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. (A.T., J.M.A.L.). The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/