Tributyltin chloride induces ABCA1 expression and apolipoprotein A-I-mediated cellular cholesterol efflux by activating LXRα/RXR

Biochem Pharmacol. 2011 Mar 15;81(6):819-24. doi: 10.1016/j.bcp.2010.12.023. Epub 2011 Jan 8.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / biosynthesis*
  • Animals
  • Apolipoprotein A-I / physiology*
  • COS Cells
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Chlorocebus aethiops
  • Cholesterol / metabolism*
  • Gene Expression Regulation
  • Liver X Receptors
  • Mice
  • Orphan Nuclear Receptors / agonists
  • Orphan Nuclear Receptors / metabolism*
  • Receptors, Retinoic Acid / agonists
  • Receptors, Retinoic Acid / metabolism
  • Trialkyltin Compounds / toxicity*

Substances

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Apolipoprotein A-I
  • Liver X Receptors
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Receptors, Retinoic Acid
  • Trialkyltin Compounds
  • tributyltin
  • Cholesterol