HDL modification by secretory phospholipase A(2) promotes scavenger receptor class B type I interaction and accelerates HDL catabolism

During inflammatory states plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) are reduced. Secretory group II a phospholipase A(2) (sPLA(2)) is a cytokine-induced acute-phase enzyme ass ociated with HDL. Transgenic mice overexpressing sPLA(2) have reduced HDL l evels. Studies were performed to define the mechanism for the HDL reduction in these mice. HDL isolated from sPLA(2) transgenic mice have a significan tly lower phospholipid content and greater triglyceride content. In autolog ous clearance studies, I-125-labeled HDL from sPLA(2) transgenic mice was c atabolized significantly faster than HDL from control mice (4.24 +/- 1.16 v s. 2.84 +/- 0.1 pools per day, P < 0.008). In both sPLA(2) transgenic and c ontrol mice, the cholesteryl ester component of HDL was more rapidly catabo lized 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 sPLA(2)-modified HDL was nearly twice as effic ient as a substrate for cholesteryl ester transfer. These data were confirm ed in in vivo selective uptake experiments using adenoviral vector overexpr ession of SR-BI. In these studies, increased hepatic selective uptake was a ssociated with increased I-125-labeled apolipoprotein uptake in the kidney. We conclude that during inflammation sPLA(2) hydrolysis of HDL phospholipi ds alters the lipid composition of the particle, allowing for more efficien t SR-BI-mediated selective cholesteryl ester uptake. This enhanced SR-BI ac tivity generates HDL remnants that are preferentially catabolized in the ki dney.