title: Proteasomal inhibition promotes ATP-binding cassette transporter A1 (ABCA1) and ABCG1 expression and cholesterol efflux from macrophages in vitro and in vivo.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Anti-aging, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Masatsune
authors.initials: M
authors.lastname: Ogura
authors.forename: Makoto
authors.initials: M
authors.lastname: Ayaori
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Terao
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hisada
authors.forename: Maki
authors.initials: M
authors.lastname: Iizuka
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takiguchi
authors.forename: Harumi
authors.initials: H
authors.lastname: Uto-Kondo
authors.forename: Emi
authors.initials: E
authors.lastname: Yakushiji
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaya
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Komatsu
authors.forename: Hideki
authors.initials: H
authors.lastname: Ozasa
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ohsuzu
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikewaki
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000502:physiology*; D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008074:Lipoproteins / Q000032:analysis / Q000502:physiology*; D008075:Lipoproteins, HDL / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D054875:Ubiquitination
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001897:Boronic Acids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D002784:Cholesterol; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex