Apolipoprotein CI aggravates atherosclerosis development in ApoE-knockout mice despite mediating cholesterol efflux from macrophages.

OBJECTIVE

Apolipoprotein CI (apoCI) is expressed in the liver and in macrophages, and has several roles in lipid metabolism. Since macrophage apoCI expression might affect macrophage lipid homeostasis and atherosclerotic lesion development locally in the arterial wall, we investigated the effect of both systemic and macrophage apoCI on atherosclerotic lesion development.

METHODS AND RESULTS

To investigate whether physiological expression levels of apoCI affect atherosclerosis development, we first assessed the effect of systemic endogenous apoCI expression on atherosclerosis in apoe-/- apoc1+/+ as compared to apoe-/- apoc1-/- mice at 26 weeks of age. ApoCI expression increased plasma levels of triglycerides (TG) (+70%; P<0.01) and cholesterol (+30%; P<0.05), and increased the atherosclerotic lesion area in the aortic root (+87%; P<0.05). Paradoxically, incubation of apoc1+/+ and apoc1-/- murine peritoneal macrophages with AcLDL (50 microg/mL; 48 h) revealed that macrophage apoCI decreased the accumulation of cellular cholesteryl esters (CE) relatively to free cholesterol (-22%; P<0.05). Accordingly, exogenous human apoCI increased cholesterol efflux from AcLDL-laden wild-type macrophages, and to a similar extent as apoAI and apoE. To evaluate whether atherosclerosis development would be affected by macrophage apoCI expression in vivo, we assessed atherosclerotic lesion development at 16 weeks after transplantation of bone marrow from apoe-/- apoc1-/- or apoe-/- apoc1+/+ mice to apoe-/- apoc1+/+ mice. However, in the situation wherein the liver and adipose tissue still produce apoCI, macrophage apoCI expression did not affect plasma lipid levels or the atherosclerotic lesion area.

CONCLUSIONS

Systemic apoCI increases atherosclerosis, probably by inducing hyperlipidemia. Despite decreasing macrophage lipid accumulation in vitro, apoCI production by macrophages locally in the arterial wall does not affect atherosclerosis development in vivo.