Increased macrophage cholesterol biosynthesis and decreased cellular paraoxonase 2 (PON2) expression in Δ6-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. Methods and 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.