Paraoxonase 1-treated oxLDL promotes cholesterol efflux from macrophages by stimulating the PPARγ-LXRα-ABCA1 pathway.

Here, we investigate the mechanism through which paraoxonase 1 (PON1) may regulate cholesterol efflux. Pretreatment of oxLDL with PON1 (oxLDL-PON1) contributed to the formation of LysoPC. In J774 macrophages, oxLDL-PON1 increased cholesterol efflux by more than 47% compared to oxLDL alone. oxLDL-PON1 significantly increased mRNA and protein expression of ABCA1 and ABCG1, as well as of PPARγ and LXRα compared to oxLDL alone. Intraperitoneal injection of oxLDL-PON1- or LysoPC-treated J774 macrophages significantly increased the fecal elimination of macrophage-derived cholesterol in these mice. Our results suggest that PON1 stimulates cholesterol efflux via a mechanism that involves oxidized phospholipid hydrolysis.