title: LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1.
abstract: The association of hypercholesterolemia and obesity with airway hyperresponsiveness has drawn increasing attention to the potential role of cholesterol and lipid homeostasis in lung physiology and in chronic pulmonary diseases such as asthma. We have recently shown that activation of the nuclear hormone receptor liver X receptor (LXR) stimulates cholesterol efflux in human airway smooth muscle (hASM) cells and induces expression of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, members of a family of proteins that mediate reverse cholesterol and phospholipid transport. We show here that ABCA1 is responsible for all LXR-mediated cholesterol and phospholipid efflux to both apolipoprotein AI and high-density lipoprotein acceptors. In contrast, ABCG1 does not appear to be required for this process. Moreover, we show that hASM cells respond to increased levels of cholesterol by inducing expression of ABCA1 and ABCG1 transporters, a process that is dependent on LXR expression. These findings establish a critical role for ABCA1 in reverse cholesterol and phospholipid transport in airway smooth muscle cells and suggest that dysregulation of cholesterol homeostasis in these cells may be important in the pathogenesis of diseases such as asthma.
authors.affiliation: Faculty of Science, Department of Biochemistry and Biomedical Sciences, 1280 Main Street W., McMaster University, Hamilton, Ontario, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Delvecchio
authors.forename: Patricia
authors.initials: P
authors.lastname: Bilan
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Nair
authors.forename: John P
authors.initials: JP
authors.lastname: Capone
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D000071518:Liver X Receptors; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D010743:Phospholipids / Q000378:metabolism; D011341:Probucol / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012137:Respiratory System / Q000378:metabolism*
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol; D011341:Probucol