Liver x receptor regulates arachidonic acid distribution and eicosanoid release in human macrophages: a key role for lysophosphatidylcholine acyltransferase 3.

نویسندگان

  • Minako Ishibashi
  • Alexis Varin
  • Rodolphe Filomenko
  • Tatiana Lopez
  • Anne Athias
  • Philippe Gambert
  • Denis Blache
  • Charles Thomas
  • Thomas Gautier
  • Laurent Lagrost
  • David Masson
چکیده

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 the release of arachidonate-derived eicosanoids, such as prostaglandin E2 and thromboxane after lipopolysaccharide stimulation, with a significant attenuation by LPCAT3 silencing. CONCLUSIONS Altogether, our data demonstrate that the LXR-mediated induction of LPCAT3 primes human macrophages for subsequent eicosanoid secretion by increasing the pool of AA, which can be mobilized from phospholipids.

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عنوان ژورنال:
  • Arteriosclerosis, thrombosis, and vascular biology

دوره 33 6  شماره 

صفحات  -

تاریخ انتشار 2013