A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis

Previous work has implicated PPAR gamma in the regulation of CD36 expressio n and macrophage uptake of oxidized LDL (oxLDL). We provide evidence here t hat in addition to lipid uptake, PPAR gamma regulates a pathway of choleste rol efflux. PPAR gamma induces ABCA1 expression and cholesterol removal fro m macrophages through a transcriptional cascade mediated by the nuclear rec eptor LXR alpha. Ligand activation of PPAR gamma leads to primary induction of LXR alpha and to coupled induction of ABCA1. Transplantation of PPAR ga mma null bone marrow into LDLR -/- mice results in a significant increase i n atherosclerosis, consistent with the hypothesis that regulation of LXR al pha and ABCA1 expression is protective in vivo. Thus, we propose that PPAR gamma coordinates a complex physiologic response to oxLDL that involves par ticle uptake, processing, and cholesterol removal through ABCA1.