title: Tributyltin chloride induces ABCA1 expression and apolipoprotein A-I-mediated cellular cholesterol efflux by activating LXRα/RXR.
abstract: Organotins, including tri-butyltin chloride (TBTC), are widely used in agricultural and chemical industries and cause persistent and widespread pollution. TBTC has been shown to activate nuclear receptor retinoid X receptor (RXR)/PPARγ signaling by interacting with RXR to modulate adipogenesis. However, whether TBTC affects liver X receptor (LXR)/RXR activity and subsequently the expression of cholesterol mobilizing genes is not known. In this study, we evaluated the ability of TBTC to activate LXR/RXR and ABC transporter A1 (ABCA1) expression. ABCA1 plays a critical role in HDL generation, maintaining cholesterol homeostasis, and cholesterol accumulation-induced diseases, such as atherosclerosis and pancreatic islet dysfunction. In a reporter gene assay, TBTC activated LXRα/RXR but not LXRβ/RXR. In mouse macrophage RAW264 cells, TBTC activated the ABCA1 promoter in an LXR-responsive element dependent manner and increased ABCA1 mRNA expression. TBTC augmented ABCA1 protein levels and apolipoprotein A-I-dependent cellular cholesterol efflux (HDL generation). The LXR-target fatty acid synthase and Spα mRNA levels were also increased by TBTC exposure. We conclude that TBTC has the ability to activate permissive LXRα/RXR signaling and thereby modulate cellular cholesterol efflux.
authors.affiliation: Division of Biochemistry and Molecular Biology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Cui
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Okuhira
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Ohoka
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Akihiko
authors.initials: A
authors.lastname: Hirose
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishimaki-Mogami
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D016632:Apolipoprotein A-I / Q000502:physiology*; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018168:Receptors, Retinoic Acid; D014220:Trialkyltin Compounds; C011559:tributyltin; D002784:Cholesterol