Human serum paraoxonase 1 decreases macrophage cholesterol biosynthesis -: Possible role for its phospholipase-A2-like activity and lysophosphatidylcholine formation

Objective-Human serum paraoxonase 1 (PON1) activity is inversely related to the risk of developing an atherosclerotic lesion, which contains cholesterol-loaded macrophage foam cells. To assess a possible mechanism for this relationship, we analyzed the effect of PON1 on cellular cholesterol biosynthesis. Methods and Results-Mouse peritoneal macrophages (MPMs) were harvested from PON1-deficient mice (PON1degrees and PON1degrees/Edegrees mice on the genetic background of C57BL/6J and Edegrees mice, respectively). PON1degrees/Edegrees mice exhibited a significantly 51% increased atherosclerotic lesion area and 35% increased macrophage cholesterol content compared with control Edegrees mice. In parallel, macrophage cholesterol biosynthesis rates were increased in PON1-deficient mice MPMs by 50% compared with their controls. Incubation of macrophages with human PON1 revealed a dose-dependent inhibitory effect (up to 84%) on macrophage cholesterol biosynthesis. We demonstrated a PON1 phospholipase-A(2)-like activity on MPMs, evidenced by release of polyunsaturated fatty acids and formation of lysophosphatidylcholine. On incubation of macrophages with lysophosphatidylcholine, a dose-dependent inhibition (up to 40%) of cellular cholesterol biosynthesis was noted. The inhibitory effect of PON1 on macrophage cholesterol biosynthesis was shown to be downstream to mevalonate, probably at the lanosterol metabolic point. Conclusions-PON1 inhibits macrophage cholesterol biosynthesis and atherogenesis probably through its phospholipase-A(2)-like activity.