title: Liver x receptor regulates arachidonic acid distribution and eicosanoid release in human macrophages: a key role for lysophosphatidylcholine acyltransferase 3.
abstract: 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.
  
  
  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.
authors.affiliation: Centre de Recherche INSERM UMR866, Université de Bourgogne, Dijon, France.
authors.forename: Minako
authors.initials: M
authors.lastname: Ishibashi
authors.forename: Alexis
authors.initials: A
authors.lastname: Varin
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Filomenko
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lopez
authors.forename: Anne
authors.initials: A
authors.lastname: Athias
authors.forename: Philippe
authors.initials: P
authors.lastname: Gambert
authors.forename: Denis
authors.initials: D
authors.lastname: Blache
authors.forename: Charles
authors.initials: C
authors.lastname: Thomas
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.forename: Laurent
authors.initials: L
authors.lastname: Lagrost
authors.forename: David
authors.initials: D
authors.lastname: Masson
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000503:physiopathology; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D046228:Microarray Analysis; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012680:Sensitivity and Specificity; D015854:Up-Regulation / Q000235:genetics
chemical_list: D015777:Eicosanoids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D016718:Arachidonic Acid; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C543069:LPCAT3 protein, human; D015232:Dinoprostone; D004121:Dimethyl Sulfoxide
keywords: arachidonic acid; liver X receptor; lysophosphatidylcholine acyltransferase; macrophages; prostaglandin E2