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Journal of Lipid Research, Vol. 41, 1849-1857, November 2000
Copyright © 2000 by Lipid Research, Inc.

Original Article

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

Correspondence to: Frederick C. de Beer

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.

Supplementary key words: high density lipoprotein, SR-BI, selective cholesteryl ester uptake, adenoviral vector

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