Proteasomal Inhibition Promotes ATP-Binding Cassette Transporter A1 (ABCA1) and ABCG1 Expression and Cholesterol Efflux From Macrophages In Vitro and In Vivo

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 31; no. 9; pp. 1980 - 1987
• Main Authors: Ogura, Masatsune, Ayaori, Makoto, Terao, Yoshio, Hisada, Tetsuya, Iizuka, Maki, Takiguchi, Shunichi, Uto-Kondo, Harumi, Yakushiji, Emi, Nakaya, Kazuhiro, Sasaki, Makoto, Komatsu, Tomohiro, Ozasa, Hideki, Ohsuzu, Fumitaka, Ikewaki, Katsunori
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.09.2011; Lippincott Williams & Wilkins
• Subjects: Animals; Apolipoprotein A-I - physiology; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Sub-Family G, Member 1; ATP-Binding Cassette Transporters - analysis; ATP-Binding Cassette Transporters - physiology; Biological and medical sciences; Blood and lymphatic vessels; Boronic Acids - pharmacology; Bortezomib; Cardiology. Vascular system; Cells, Cultured; Cholesterol - metabolism; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Hep G2 Cells; Humans; Lipoproteins - analysis; Lipoproteins - physiology; Lipoproteins, HDL - physiology; Macrophages - metabolism; Medical sciences; Mice; Phosphorylation; Proteasome Endopeptidase Complex - physiology; Proteasome Inhibitors; Pyrazines - pharmacology; Ubiquitin-Protein Ligases - physiology; Ubiquitination; reverse cholesterol transport; Lipids; Cardiovascular disease; Macrophages; Cholesterol; Vascular disease; HDL; ubiquitin-proteasome system; ABC Transporter; Atherosclerosis; Lipoprotein HDL; Transport; ATP; Macrophage
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.111.228478

OBJECTIVE—ATP-binding cassette transporter A1 (ABCA1) and ABCG1 are key molecules in an initial step of reverse cholesterol transport (RCT), a major antiatherogenic property of high-density lipoprotein (HDL). The ubiquitin-proteasome system (UPS) mediates nonlysosomal pathways for protein degradation and is known to be involved in atherosclerosis. However, little is known about the effects of the UPS on these molecules and overall RCT. We therefore investigated whether UPS inhibition affects ABCA1/G1 expression in macrophages and RCT in vitro and in vivo. METHODS AND RESULTS—Various proteasome inhibitors increased ABCA1/G1 expression in macrophages, translating into enhanced apolipoprotein A-I– and HDL-mediated cholesterol efflux from macrophages. ABCA1 and ABCG1 were found to undergo polyubiquitination in the macrophages and HEK293 cells overexpressing these proteins, and pulse-chase analysis revealed that proteasome inhibitors inhibited ABCA1/G1 protein degradation. In in vivo experiments, the proteasome inhibitor bortezomib increased ABCA1/G1 protein levels in mouse peritoneal macrophages, and RCT assays showed that it significantly increased the fecal (54% increase compared with saline) and plasma (23%) appearances of the tracer derived from intraperitoneally injected H-cholesterol-labeled macrophages. CONCLUSION—The present study provided evidence that the UPS is involved in ABCA1/G1 degradation, thereby affecting RCT in vivo. Therefore, specific inhibition of the UPS pathway might lead to a novel HDL therapy that enhances RCT.