Group X secretory phospholipase A2 negatively regulates ABCA1 and ABCG1 expression and cholesterol efflux in macrophages

Preetha Shridas, William M. Bailey, Florence Gizard, Rob C. Oslund, Michael H. Gelb, Dennis Bruemmer, Nancy R. Webb

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Objective-: GX sPLA2 potently hydrolyzes plasma membranes to generate lysophospholipids and free fatty acids; it has been implicated in inflammatory diseases, including atherosclerosis. To identify a novel role for group X (GX) secretory phospholipase A2 (sPLA2) in modulating ATP binding casette transporter A1 (ABCA1) and ATP binding casette transporter G1 (ABCG1) expression and, therefore, macrophage cholesterol efflux. Methods and results-: The overexpression or exogenous addition of GX sPLA 2 significantly reduced ABCA1 and ABCG1 expression in J774 macrophage-like cells, whereas GX sPLA2 deficiency in mouse peritoneal macrophages was associated with enhanced expression. Altered ABC transporter expression led to reduced cholesterol efflux in GX sPLA 2-overexpressing J774 cells and increased efflux in GX sPLA 2-deficient mouse peritoneal macrophages. Gene regulation was dependent on GX sPLA2 catalytic activity, mimicked by arachidonic acid and abrogated when liver X receptor (LXR)α/β expression was suppressed, and partially reversed by the LXR agonist T0901317. Reporter assays indicated that GX sPLA2 suppresses the ability of LXR to transactivate its promoters through a mechanism involving the C-terminal portion of LXR spanning the ligand-binding domain. Conclusion-: GX sPLA2 modulates gene expression in macrophages by generating lipolytic products that suppress LXR activation. GX sPLA2 may play a previously unrecognized role in atherosclerotic lipid accumulation by negatively regulating the genes critical for cellular cholesterol efflux.

Original languageEnglish
Pages (from-to)2014-2021
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume30
Issue number10
DOIs
StatePublished - Oct 2010

Keywords

  • ABC transporter
  • LXR
  • cholesterol efflux
  • fatty acids
  • lipases
  • lipoproteins
  • macrophages
  • prostaglandins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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