Genetic deletion of LDL receptor impairs mouse macrophage ABCA1 expression and cholesterol efflux: A new SREBP‐1 dependent mechanism

• Published in: The FASEB journal 2007-04, Vol.21 (5), p.A16-A16
• Main Authors: Han, Jihong, He, Wei, Zhou, Xiaoye, Huang, Zhiping, Nicholson, Andrew C, Gotto, Antonio M, Hajjar, David P
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.21.5.A16-c

LDLR mutations cause familial hypercholesterolemia and early atherosclerosis. Since ABCA1 facilitates free cholesterol efflux from peripheral tissues, we set out to investigate the effects of LDLR deletion (LDLR−/−) on macrophage ABCA1 expression and cholesterol efflux. LDLR−/− macrophages had reduced basal levels of ABCA1 and cholesterol efflux. High‐fat diet increased cholesterol in LDLR−/− macrophages, but not in wild type cells. LXR agonist induced ABCA1 expression and cholesterol efflux in LDLR−/− macrophages, and modified lipoproteins induced ABCA1 expression in both cell types. Conversely, LDL induced ABCA1 expression in wild type but inhibited it in LDLR−/− macrophages, while free cholesterol stimulated ABCA1 expression in wild type but had no effect on LDLR−/− macrophages. 25‐hydroxycholesterol inhibited SREBP‐1 in wild type macrophages but activated it in LDLR−/− cells, and regulated ABCA1 expression differently in these two cell types. Inhibition of SREBP‐1 by siRNA induced ABCA1 expression and cholesterol efflux. Taken together, our studies suggest that LDLR is critical in the regulation of macrophage cholesterol efflux and ABCA1 expression. We believe that absence of the LDLR suppresses ABCA1 expression and cholesterol efflux under condition of hypercholesterolemia. This may contribute to lipid accumulation in macrophages during the development of atherosclerosis.