title: Expression of ATP binding cassette-transporter ABCG1 prevents cell death by transporting cytotoxic 7beta-hydroxycholesterol.
abstract: Oxysterols result from cholesterol by enzymatic or oxidative processes. Some exert cytotoxic effects leading to necrosis or apoptosis. Detoxification of these compounds mainly occurs in the liver and requires transport from peripheral tissues towards it. Some ATP-binding cassette transporters are involved in export of cytotoxic compounds. In the current study, we investigated whether ABC transporter family member G1 (ABCG1) may be involved in oxysterol transport, since its gene expression is highly responsive to oxysterol loading. TetOff HeLa cells stably expressing ABCG1 showed decreased mass uptake of 7beta-hydroxycholesterol (7beta-HC) whereas that of other physiologically relevant oxysterols was unaffected. Application of 7beta-HC to ABCG1 expressing cells induced hyperpolarization of mitochondrial membrane potential and production of reactive oxygen species, indicating energy consumption by the ATP-binding cassette transporter when it is activated by its correct substrate. Our study points to detoxification as one of potential cellular functions of ABCG1. We assume that ABCG1 protects against 7beta-HC-induced cell death, an important role in prevention of neurodegenerative and cardiovascular disease.
authors.affiliation: Leibniz-Institute for Arteriosclerosis Research, Westphalian Wilhelms-University, 48149 Muenster, Germany. engeltho@uni-muenster.de <engeltho@uni-muenster.de>
authors.forename: Thomas
authors.initials: T
authors.lastname: Engel
authors.forename: Frank
authors.initials: F
authors.lastname: Kannenberg
authors.forename: Manfred
authors.initials: M
authors.lastname: Fobker
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
authors.forename: Guenther
authors.initials: G
authors.lastname: Bode
authors.forename: Aloys
authors.initials: A
authors.lastname: Lueken
authors.forename: Gerd
authors.initials: G
authors.lastname: Assmann
authors.forename: Udo
authors.initials: U
authors.lastname: Seedorf
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001692:Biological Transport; D002318:Cardiovascular Diseases / Q000209:etiology; D016923:Cell Death; D006367:HeLa Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D008564:Membrane Potentials; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000209:etiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D006888:Hydroxycholesterols; D017382:Reactive Oxygen Species; C011724:cholest-5-en-3 beta,7 alpha-diol