title: HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7.
abstract: We recently reported that the endogenous ATP-binding cassette transporter (ABC) A7 strongly associates with phagocytosis, being regulated by sterol regulatory element binding protein 2. We therefore examined the effect of statins on phagocytosis in vitro and in vivo through the SREBP-ABCA7. Phagocytosis was found to be enhanced by pravastatin, rosuvastatin and simvastatin and cyclodextrin in J774 macrophages, as cellular cholesterol was reduced and expressions of the cholesterol-related genes were modulated, including an increase of ABCA7 mRNA and decrease of ABCA1 mRNA. Conversely, knock-down of ABCA7 expression by siRNA ablated enhancement of phagocytosis by statins. In vivo, pravastatin enhanced phagocytosis in wild-type mice, but not in ABCA7-knockout mice. We thus concluded that statins enhance phagocytosis through the SREBP-ABCA7 pathway. These findings provide a molecular basis for enhancement of the host-defense system by statins showing that one of their "pleiotropic" effects is in fact achieved through their reaction to a primary target.
authors.affiliation: Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan.
authors.forename: Nobukiyo
authors.initials: N
authors.lastname: Tanaka
authors.forename: Sumiko
authors.initials: S
authors.lastname: Abe-Dohmae
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Iwamoto
authors.forename: Michael L
authors.initials: ML
authors.lastname: Fitzgerald
authors.forename: Shinji
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D005464:Fluorobenzenes / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D019169:Jurkat Cells; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000187:drug effects*; D017035:Pravastatin / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D015854:Up-Regulation
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; C485856:Abca7 protein, mouse; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D019821:Simvastatin; D017035:Pravastatin