Group X Secretory Phospholipase A ₂ Negatively Regulates ABCA1 and ABCG1 Expression and Cholesterol Efflux in Macrophages

Abstract

Objectives Group X secretory phospholipase A2 (GX sPLA2) potently hydrolyzes plasma membranes to generate lysophospholipids and free fatty acids and has been implicated in inflammatory diseases including atherosclerosis. Here we identify a novel role for GX sPLA2 in modulating ABCA1 and ABCG1 expression and hence macrophage cholesterol efflux. Methods and Results Overexpression or exogenous addition of GX sPLA2 significantly reduced ABCA1 and ABCG1 expression in J774 macrophage-like cells, whereas GX sPLA2 deficiency in mouse peritoneal macrophages (MPMs) was associated with enhanced expression. Altered ABC transporter expression led to reduced cholesterol efflux in GX sPLA2 overexpressing J774 cells, and increased efflux in GX sPLA2-deficient MPMs. Gene regulation was dependent on GX sPLA2 catalytic activity, mimicked by arachidonic acid, abrogated when LXRα/β expression was suppressed, and partially reversed by the LXR agonist T0901317. Reporter assays indicated that GX sPLA2 suppresses the ability of LXR to trans-activate its promoters through a mechanism involving the C-terminal portion of LXR spanning the ligand binding domain. Conclusions 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 genes critical for cellular cholesterol efflux.

Group X Secretory Phospholipase A2 Regulates Insulin Secretion through a Cyclooxygenase-2-dependent Mechanism

“…We and others have reported that GX sPLA 2 potently releases arachidonic acid (AA) and thus enhances PGE2 production in multiple cell types (30,32,33). Here we show that increased GX sPLA 2 activity leads to enhanced PGE2 production in beta cells.…”

“…7). We previously reported that GX sPLA 2 modulates cellular functions by negatively regulating LXR activity in macrophages, adrenal cells, and fat cells (30,31,43). The LXR target genes ABCA1 and ABCG1 play critical roles in maintaining beta cell function by regulating cellular cholesterol homeostasis.…”

“…L-798,106 was from Santa Cruz Biotechnology. Animals-We previously described the generation of C57BL/6 mice with targeted deletion of GX sPLA 2 (gene PLA2G10) (30). Heterozygous GX sPLA 2 ϩ/Ϫ mice were bred to produce GX sPLA 2 ϩ/ϩ (WT) and GX sPLA 2 Ϫ/Ϫ (GX KO) mice for the experiments.…”

Ectopically Expressed Pro-group X Secretory Phospholipase A2 Is Proteolytically Activated in Mouse Adrenal Cells by Furin-like Proprotein Convertases

“…Are Overexpressed-We previously reported that GX sPLA 2 inhibits LXR-mediated target gene activation through a mechanism that is dependent on its enzymatic activity (10). Therefore, we investigated whether proteolytic activation of GX sPLA 2 by furin or PCSK6 enhances GX sPLA 2 -dependent inhibition of LXR activation.…”

“…We also determined that GX sPLA 2 suppresses LXR activation in macrophages, resulting in reduced expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) (10). Consequently, macrophages from GX KO mice exhibit increased cellular cholesterol efflux and decreased cellular cholesterol content (10). GX sPLA 2 is expressed in adrenal cells, where it suppresses corticosteroid production through a mechanism that also appears to involve LXR.…”