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Journal of Lipid Research, Vol. 46, 2377-2387, November 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Downregulation of liver X receptor- in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines

Yuwei Wang, Arthur H. Moser, Judy K. Shigenaga, Carl Grunfeld and Kenneth R. Feingold¹

Department of Medicine, University of California San Francisco, and Metabolism Section, Department of Veterans Affairs Medical Center, San Francisco, CA 94121

Published, JLR Papers in Press, August 16, 2005. DOI 10.1194/jlr.M500134-JLR200

¹ To whom correspondence should be addressed. e-mail: kfngld{at}itsa.ucsf.edu

The acute-phase response (APR) suppresses type II nuclear hormone receptors and alters the expression of their target genes involved in lipid metabolism in the liver and heart. Therefore, we examined the expression of liver X receptor/retinoid X receptor (LXR/RXR) and their target genes in kidney from mice treated with lipopolysaccharide (LPS) and in human proximal tubular HK-2 cells treated with interleukin-1ß (IL-1ß) and tumor necrosis factor- (TNF-). We found that LXR and RXR expression was suppressed by LPS in kidney and by IL-1ß or TNF- in HK-2 cells. The decrease in LXR/RXR expression was associated with a decrease in the expression of several LXR target genes [apolipoprotein E (apoE), ABCA1, ABCG1, and sterol-regulatory element binding protein-1c (SREBP-1c)] and a decrease in ligand-induced apoE expression. Moreover, IL-1ß and TNF- significantly reduced liver X receptor response element (LXRE)-driven transcription as measured by LXRE-linked luciferase activity. However, overexpression of LXR/RXR only partially restored the cytokine-mediated reduction in LXRE-linked luciferase activity. Additionally, expression of the LXR coactivators peroxisome proliferator-activated receptor coactivator 1 (PGC1) and steroid receptor coactivator-2 (SRC-2) was decreased by IL-1ß or TNF-.

We conclude that the APR suppresses the expression of both nuclear receptors LXR/RXR and several LXR coactivators in kidney, which could be a mechanism for coordinately regulating the expression of multiple LXR target genes that play important roles in lipid metabolism in kidney during the APR.

Abbreviations: apoE, apolipoprotein E; APR, acute-phase response; FXR, farnesoid X receptor; IL, interleukin; LPS, lipopolysaccharide; LXR, liver X receptor; LXRE, liver X receptor response element; PGC-1, peroxisome proliferator-activated receptor coactivator 1; PPAR, peroxisome proliferator-activated receptor; PTC, proximal tubular cell; RXR, retinoid X receptor; SRC, steroid receptor coactivator; SREBP-1c, sterol-regulatory element binding protein-1c; TNF, tumor necrosis factor

Supplementary key words lipopolysaccharide • acute-phase response • lipid metabolism

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