Macrophage paraoxonase 2 (PON2) expression is upregulated by unesterified cholesterol through activation of the phosphatidylinositol 3-kinase (PI3K) pathway.

Advanced atherosclerotic lesions are characterized by a progressive increase in the unesterified cholesterol (UC) content and a decrease in its cholesteryl ester (CE) content. In the present study, we examined mechanisms involved in the effect of UC and CE on the expression of paraoxonase 2 (PON2) in macrophages. J774A.1 macrophages were enriched with CE or UC by incubation for 14-48 h with 50 microg acetylated low-density lipoprotein in the absence or presence of the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor 58035 (50 microg/ml), respectively. Macrophage PON2 mRNA expression, protein abundance and activity were increased only in the UC-enriched cells. In UC-enriched cells, inhibition of phosphatidylinositol 3-kinase (PI(3)K; using wortmannin or LY294002) attenuated the increase in PON2 mRNA expression by 50%, compared to untreated cells. In addition, we evidenced an increased phosphorylation of Akt in UC-enriched cells. Thus, we conclude from our data that macrophage PON2 expression is upregulated in UC-enriched macrophages through activation of the PI(3)K signal pathway.