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Journal of Lipid Research, Vol. 43, 1054-1064, July 2002
Copyright © 2002 by Lipid Research, Inc.
LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells
Department of Veterans Affairs and Department of Internal Medicine, University of Iowa, Iowa City, IA 52242
1 To whom correspondence should be addressed. e-mail: shubha-murthy{at}uiowa.edu
Regulation of gene expression of ATP-binding cassette transporter (ABC)A1 and ABCG1 by liver X receptor/retinoid X receptor (LXR/RXR) ligands was investigated in the human intestinal cell line CaCo-2. Neither the RXR ligand, 9-cis retinoic acid, nor the natural LXR ligand 22-hydroxycholesterol alone altered ABCA1 mRNA levels. When added together, ABCA1 and ABCG1 mRNA levels were increased 3- and 7-fold, respectively. T0901317, a synthetic non-sterol LXR agonist, increased ABCA1 and ABCG1 gene expression 11- and 6-fold, respectively. ABCA1 mass was increased by LXR/RXR activation. T0901317 or 9-cis retinoic acid and 22-hydroxycholesterol increased cholesterol efflux from basolateral but not apical membranes. Cholesterol efflux was increased by the LXR/RXR ligands to apolipoprotein (apo)A-I or HDL but not to taurocholate/phosphatidylcholine micelles. Actinomycin D prevented the increase in ABCA1 and ABCG1 mRNA levels and the increase in cholesterol efflux induced by the ligands. Glyburide, an inhibitor of ABCA1 activity, attenuated the increase in basolateral cholesterol efflux induced by T0901317. LXR/RXR activation decreased the esterification and secretion of cholesterol esters derived from plasma membranes.
Thus, in CaCo-2 cells, LXR/RXR activation increases gene expression of ABCA1 and ABCG1 and the basolateral efflux of cholesterol, suggesting that ABCA1 plays an important role in intestinal HDL production and cholesterol absorption.
Abbreviations: ABC, ATP-binding cassette transporter; ACAT, acyl-CoA:cholesterol acyltransferase; ActD, actinomycin D; apo, apolipoprotein; FC, free cholesterol; LXR, liver X receptor; MTP, microsomal triglyceride transfer protein; RXR, retinoid X receptor; TC/PC, taurocholate micelles containing phosphatidylcholine; 9cRA, 9-cis retinoic acid; 22OHC, 22-hydroxycholesterol
Supplementary key words liver X receptor • retinoid X receptor • 9-cis retinoic acid • 22-hydroxycholesterol • T0901317 • ABCA1 • ABCG1 • apolipoprotein A-I • high density lipoprotein • cholesterol absorption
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