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 IIa phospholipase A(2) (sPLA(2)) is a cytokine-induced acute-phase enzyme associated with HDL. Transgenic mice overexpressing sPLA(2) have reduced HDL levels. Studies were performed to define the mechanism for the HDL reduction in these mice. HDL isolated from sPLA(2) transgenic mice have a significantly lower phospholipid content and greater triglyceride content. In autologous clearance studies, (125)I-labeled HDL from sPLA(2) 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 sPLA(2) 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 sPLA(2)-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 (125)I-labeled apolipoprotein uptake in the kidney. We conclude that during inflammation sPLA(2) 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
FC
Department of Internal Medicine, University of Kentucky Medical Center, Lexington, KY 40536, USA.
Connell
P M
PM
Yu
J
J
de Beer
M C
MC
Webb
N R
NR
van der Westhuyzen
D R
DR
D000818:Animals; D018955:CD36 Antigens; D016466:CHO Cells; D002788:Cholesterol Esters / Q000378:metabolism; D006224:Cricetinae; D015870:Gene Expression; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000032:analysis / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010741:Phospholipases A / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000032:analysis; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D014162:Transfection; D014280:Triglycerides / Q000032:analysis; D014316:Tritium; D014439:Tyramine / Q000031:analogs & derivatives* / Q000378:metabolism
D018955:CD36 Antigens; D002788:Cholesterol Esters; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D010743:Phospholipids; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; D014316:Tritium; C049133:dilactitol tyramine; D010741:Phospholipases A; D014439:Tyramine