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.

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.

• Authors: Alexis Varin, Charles Thomas, Minako Ishibashi, Louise Ménégaut, Thomas Gautier, Amalia Trousson, Victoria Bergas, Jean Paul Pais de Barros, Michel Narce, Jean Marc A Lobaccaro, Laurent Lagrost, David Masson
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 35 Issue 6 Pg. 1357-65 (Jun 2015) ISSN: 1524-4636 [Electronic] United States
• PMID: 25838428 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Fatty Acids, Unsaturated
• Liver X Receptors
• Orphan Nuclear Receptors
• Sterol Regulatory Element Binding Protein 1
• Arachidonic Acid

Topics

• Animals
• Arachidonic Acid (metabolism)
• Arteries (metabolism)
• Atherosclerosis (metabolism)
• Fatty Acids, Unsaturated (biosynthesis)
• Foam Cells (metabolism)
• Humans
• Liver X Receptors
• Macrophages (metabolism)
• Mice
• Orphan Nuclear Receptors (agonists, metabolism)
• Sterol Regulatory Element Binding Protein 1 (metabolism)