HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway

• Published in: The Journal of clinical investigation Vol. 116; no. 5; pp. 1435 - 1442
• Main Author: Matsuura, F.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.05.2006
• Subjects: Animals; Apolipoproteins E - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters - metabolism; Biomedical research; Carrier Proteins - genetics; Carrier Proteins - physiology; Cholesterol; Cholesterol - metabolism; Cholesterol Ester Transfer Proteins; DNA-Binding Proteins - metabolism; Foam Cells - metabolism; Genetic research; Glycoproteins - genetics; Glycoproteins - physiology; High density lipoprotein; Humans; Lipids; Lipoproteins, HDL - chemistry; Liver; Liver X Receptors; Low density lipoprotein; Male; Medical research; Medicine, Experimental; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Phosphatidylcholine-Sterol O-Acyltransferase - metabolism; Plasma; Proteins; Receptors, Cytoplasmic and Nuclear - metabolism; Japan
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI27602

Genetic deficiency or inhibition of cholesteryl ester transfer protein (CETP) leads to a marked increase in plasma levels of large HDL-2 particles. However, there is concern that such particles may be dysfunctional in terms of their ability to promote cholesterol efflux from macrophages. Recently, the ATP-binding cassette transporter ABCG1, a macrophage liver X receptor (LXR) target, has been shown to stimulate cholesterol efflux to HDL. We have assessed the ability of HDL from subjects with homozygous deficiency of CETP (CETP-D) to promote cholesterol efflux from macrophages and have evaluated the role of ABCG1 and other factors in this process. CETP-D HDL-2 caused a 2- to 3-fold stimulation of net cholesterol efflux compared with control HDL-2 in LXR-activated macrophages, due primarily to an increase in lecithin:cholesterol acyltransferase-mediated (LCAT-mediated) cholesteryl ester formation in media. Genetic knockdown or overexpression of ABCG1 showed that increased cholesterol efflux to CETP-D HDL was ABCG1 dependent. LCAT and apoE contents of CETP-D HDL-2 were markedly increased compared with control HDL-2, and increased cholesterol esterification activity resided within the apoE-HDL fraction. Thus, CETP-D HDL has enhanced ability to promote cholesterol efflux from foam cells in an ABCG1-dependent pathway due to an increased content of LCAT and apoE.