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.
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
Bianca
B
Fuhrman
Anna
A
Gantman
Michael
M
Aviram
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