HDL modification by secretory phospholipase A2 promotes scavenger receptor class B type I interaction and accelerates HDL catabolism

Abstract

During inflammatory states plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) are reduced. Secretory group IIa phospholipase A2 (sPLA2) is a cytokine-induced acute-phase enzyme associated with HDL. Transgenic mice overexpressing sPLA2 have reduced HDL levels. Studies were performed to define the mechanism for the HDL reduction in these mice. HDL isolated from sPLA2 transgenic mice have a significantly lower phospholipid content and greater triglyceride content. In autologous clearance studies, 125I-labeled HDL from sPLA2 transgenic mice was catabolized significantly faster than HDL from control mice (4.24 ± 1.16 vs. 2.84 ± 0.1 pools per day, P < 0.008). In both sPLA2 transgenic and control mice, the cholesteryl ester component of HDL was more rapidly catabolized than the protein component, indicating a selective uptake mechanism. In vitro studies using CHO cells transfected with scavenger receptor class B type I (SR-BI) showed that sPLA2-modified HDL was nearly twice as efficient as a substrate for cholesteryl ester transfer. These data were confirmed in in vivo selective uptake experiments using adenoviral vector overexpression of SR-BI. In these studies, increased hepatic selective uptake was associated with increased 125I-labeled apolipoprotein uptake in the kidney. We conclude that during inflammation sPLA2 hydrolysis of HDL phospholipids alters the lipid composition of the particle, allowing for more efficient SR-BI-mediated selective cholesteryl ester uptake. This enhanced SR-BI activity generates HDL remnants that are preferentially catabolized in the kidney.—de Beer, F. C., P. M. Connell, J. Yu, M. C. de Beer, N. R. Webb, and D. R. van der Westhuyzen. HDL modification by secretory phospholipase A2 promotes scavenger receptor class B type I interaction and accelerates HDL catabolism. J. Lipid Res. 2000. 41: 1849–1857.

Keywords

• high density lipoprotein
• SR-BI
• selective cholesteryl ester uptake
• adenoviral vector