Phospholipase A2 group IIA correlates with circulating high-density lipoprotein cholesterol and modulates cholesterol efflux possibly through regulation of PPAR-γ/LXR-α/ABCA1 in macrophages

Abstract

Background Secretory phospholipase A2 group IIA (sPLA2-IIA) is an independent risk factor for cardiovascular disease, but its role on high-density lipoprotein cholesterol (HDL-C) level has not been clarified. The aim of the present study was to explore the association between circulating sPLA2-IIA and HDL-C, and to evaluate if sPLA2-IIA enhances cholesterol efflux capacity through regulation of peroxisome proliferator-activated receptor γ (PPAR-γ), liver X receptor α (LXR-α), and ATP-binding cassette A1 (ABCA1). Methods 131 patients with coronary artery disease were enrolled. The plasma level of sPLA2-IIA was tested with enzyme-linked immunosorbent assay kit, and serum lipids were assessed by biochemical analyzer. Human monocyte-macrophage cell line THP-1 was co-incubated with sPLA2-IIA in the presence/absence of selective PPAR-γ antagonist GW9662 in vitro. Real-time PCR and Western-blot were employed to measure the mRNA and protein expressions of PPAR-γ, LXR-α, and ABCA1, respectively. The cholesterol efflux was evaluated by using an assay kit. Results In subjects, circulating level of sPLA2-IIA was positively related with that of HDL-C (r = 0.196, p = 0.024). The plasma level of sPLA2-IIA was significantly higher in the high HDL-C (≥ 1.04 mmol/L) group (7477.828 pg/mL) than that in low HDL-C (< 1.04 mmol/L) group (5836.92 pg/mL, p = 0.004). For each increase of 1 pg/μl in sPLA2-IIA level, the adjusted odds ratio for HDL-C ≥ 1.04 mmol/L was 1.143. Co-incubation of THP-1 cells with sPLA2-IIA resulted in increased expressions of PPAR-γ, LXR-α, and ABCA1, as well as enhanced cholesterol efflux capacity, that were all reversed by administration of GW9662. Conclusions Circulating sPLA2-IIA was positively associated with HDL-C. PPAR-γ/LXR-α/ABCA1 might be responsible for sPLA2-IIA-regulated cholesterol efflux in macrophages.

The roles of nuclear receptors in cholesterol metabolism and reverse cholesterol transport in nonalcoholic fatty liver disease

“… 240 An investigation of 131 patients with coronary artery disease also revealed that the use of the PPARγ inhibitor GW9662 led to a decrease in LXR-α and ABCA1 levels in the group, accompanied by impaired cholesterol efflux capacity. 241 Cholesterol carried by HDL is eventually taken up by hepatic SR-B1 receptors after circulation and metabolized in the liver, which brings us back to the liver function discussed at the beginning of this review.…”

Partial Synthetic PPARƳ Derivative Ameliorates Aorta Injury in Experimental Diabetic Rats Mediated by Activation of miR-126-5p Pi3k/AKT/PDK 1/mTOR Expression

“…The nuclear receptor superfamily includes ligand-activated transcription factors called peroxisome proliferator-activated receptors (PPARs) [ 28 ]; the PPAR family is subdivided into three isotypes PPARα, PPAR β/δ, and PPARƳ [ 41 ]. Activation of the PPARs subtype is essential for controlling cell proliferation, differentiation, apoptosis [ 42 ], enhancing cell development [ 43 ], and wound healing [ 44 ], raising high-density lipoprotein (HDL) levels [ 45 ], reducing triglyceride levels [ 46 ], and improving insulin sensitivity [ 47 ]. However, PPARα is widely distributed throughout the body tissues such as cardiac [ 48 ], renal, liver [ 49 ], muscles, and adipose tissue [ 50 ], which is essential for regulation of angiogenesis, inflammation, and free fatty acid catabolism [ 51 ].…”