Increased macrophage cholesterol biosynthesis and decreased cellular paraoxonase 2 (PON2) expression in Delta6-desaturase knockout (6-DS KO) mice: beneficial effects of arachidonic acid.
OBJECTIVE
To analyze the possible role of arachidonic acid (AA) in macrophage cholesterol biosynthesis and in PON2 expression.


RESULTS
We used peritoneal macrophages (MPM) from the 6-DS KO mice that were fed a diet without or with AA. Macrophage cholesterol biosynthesis rate and HMGCoA-reductase mRNA levels were substantially increased, by 98% and 67%, respectively, in MPM from 6-DS KO vs. control (C57BL/6) mice. Furthermore, in the 6-DS KO vs. control mice MPM PON2 expression (mRNA and lactonase activity) was substantially decreased. In line with the above results, AA supplementation to 6-DS KO mice significantly decreased MPM cholesterol biosynthesis rate and HMGCoA-reductase mRNA levels, by 45% and by 4-fold respectively, and increased MPM PON2 lactonase activity and PON2 mRNA, by 119% and 2.3-fold, respectively. Similarly, incubation of control mice MPM or J774A.1 with AA, significantly and dose-dependently decreased cellular cholesterol biosynthesis rate, and increased PON2 expression. These effects were specific for AA since incubation of the cells with docosahexaenoic acid (DHA, another product of 6-DS) had no significant effects on cholesterol biosynthesis rate, and on PON2 activity.


CONCLUSIONS
AA decreased macrophage cholesterol biosynthesis rate, and increased PON2 expression. These effects could protect the cells from cholesterol accumulation and oxidation, and from foam cell formation, the hallmark of early atherogenesis.
Rosenblat
Mira
M
The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, 31096 Haifa, Israel.
Volkova
Nina
N
Roqueta-Rivera
Manuel
M
Nakamura
Manabu T
MT
Aviram
Michael
M
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D050197:Atherosclerosis; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005487:Foam Cells / Q000166:cytology; D050602:Linoleoyl-CoA Desaturase / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological
D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D002784:Cholesterol; D050602:Linoleoyl-CoA Desaturase; D043303:Aryldialkylphosphatase