Proteasomal Inhibition Promotes ATP-Binding Cassette Transporter A1 (ABCA1) and ABCG1 Expression and Cholesterol Efflux From Macrophages In Vitro and In Vivo
| Autor: | Kazuhiro Nakaya, Tetsuya Hisada, Yoshio Terao, Emi Yakushiji, Fumitaka Ohsuzu, Makoto Sasaki, Masatsune Ogura, Makoto Ayaori, Shunichi Takiguchi, Hideki Ozasa, Harumi Uto-Kondo, Katsunori Ikewaki, Tomohiro Komatsu, Maki Iizuka |
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| Rok vydání: | 2011 |
| Předmět: |
Proteasome Endopeptidase Complex
Lipoproteins Ubiquitin-Protein Ligases ATP-binding cassette transporter Bortezomib Mice In vivo Animals Humans Phosphorylation Cells Cultured ATP Binding Cassette Transporter Subfamily G Member 1 Apolipoprotein A-I biology Macrophages Reverse cholesterol transport Ubiquitination Transporter Hep G2 Cells Boronic Acids Cholesterol ATP Binding Cassette Transporter 1 ABCG1 Biochemistry Pyrazines ABCA1 biology.protein ATP-Binding Cassette Transporters lipids (amino acids peptides and proteins) Efflux Lipoproteins HDL Cardiology and Cardiovascular Medicine Proteasome Inhibitors |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 31:1980-1987 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | 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 3 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. |
| Databáze: | OpenAIRE |
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