The macrophage sterol transport protein ORP2 promotes cholesterol efflux and prevents foam cell formation and atherosclerosis

Cholesterol-loaded macrophage foam cells are a key feature of atherosclerotic plaques. Oxysterol-binding protein-related protein 2 (ORP2) facilitates the transport of cholesterol from lysosomes to the plasma membrane in cultured cell lines. However, the role of ORP2 in macrophages and its involvement in atherosclerosis remain unclear. In this study, we found ORP2 expression was reduced in atherosclerotic vessels and in macrophages exposed to oxidized LDL (ox-LDL). Myeloid-specific human ORP2 overexpression (hORP2^MOE) mice were generated and crossed with atherosclerotic-prone ApoE^-/- mice and then fed a high-fat diet (HFD) to induce atherosclerosis. Our results showed that myeloid-specific hORP2 overexpression significantly reduced the atherosclerotic plaque area, along with reduced lipid accumulation, necrotic core size, birefringent crystals, and macrophage presence within the plaque. Additionally, hORP2 overexpression in peritoneal macrophages (PMCs) led to reduced lipid accumulation and increased expression of key cholesterol efflux proteins, including LXRα, ABCA1, and ABCG1. Furthermore, hOPR2 overexpression promoted NBD-cholesterol efflux from macrophages. To explore the underlying mechanism, we conducted co-immunoprecipitation, immunofluorescence, and cytoplasmic/nuclear fractionation experiments. Our findings revealed that ORP2 interacts with LXRα and promotes its nuclear localization in macrophages. Moreover, the LXR antagonist GSK2033 blocked the reduction in foam cell formation and the increase in LXRα nuclear translocation induced by hORP2 overexpression. These findings suggest that ORP2 interacts with LXRα and facilitates its nuclear translocation in macrophages, leading to reduced foam cell formation and alleviation of atherosclerosis.