Paraoxonase 1 (PON1) deficiency in mice is associated with reduced expression of macrophage SR-BI and consequently the loss of HDL cytoprotection against apoptosis.
BACKGROUND
Paraoxonase 1 (PON1) was shown to stimulate HDL binding and HDL-mediated cholesterol efflux from macrophages. This study examined the role of PON1 in the expression of proteins that enhance macrophage HDL binding, i.e. ABCA1 and SR-BI.


RESULTS
ABCA1 expression was similar, whereas SR-BI expression (mRNA and protein determined by FACS, Western blot, or immunocytochemistry) was significantly decreased in peritoneal macrophages from PON1 deficient (MPM-PON1(0)) in comparison to C57Bl/6 (MPM-Control) mice. PON1 deficiency correction with HDL-control, recombinant PON1 (rePON1), or by transfection with a plasmid containing the rePON1 gene, increased SR-BI expression in MPM-PON1(0), whereas rePON1/H115Gln mutant, or the H115Q/H134Q double mutant, which lack catalytic activity, did not stimulate SR-BI expression. Lysophosphatidyl choline (LPC) resulting from PON1 action on macrophage PC, upregulated SR-BI expression in MPM-PON1(0) via activation of ERK1/2 and PI3K. Functionally, HDL bound to MPM-PON1(0) significantly less than to MPM-Control, and failed to inhibit tunicamycin-induced apoptosis, but had no significant effect on HDL-mediated cholesterol efflux from macrophages.


CONCLUSIONS
PON1 deficiency in mice is associated with decreased macrophage SR-BI expression, decreased cellular HDL binding, and consequently the loss of HDL-mediated cytoprotection against apoptosis, which may contribute to the accelerated atherosclerosis observed in PON1(0) mice. These findings add new insights into the function of SR-BI in macrophages, and define the potential role of PON1 in regulating SR-BI-mediated HDL protection against macrophages apoptosis.
Fuhrman
Bianca
B
The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, 31096 Haifa, Israel. Fuhrman@tx.technion.ac.il
Gantman
Anna
A
Aviram
Michael
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D043303:Aryldialkylphosphatase / Q000172:deficiency* / Q000235:genetics; D002460:Cell Line; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis*; D015854:Up-Regulation
D008075:Lipoproteins, HDL; D008244:Lysophosphatidylcholines; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D043303:Aryldialkylphosphatase