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Papers In Press, published online ahead of print August 16, 2005
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Medicine, Department of Veterans Affairs Medical Center,, University of California, San Francisco, San Francisco, CA 94121
Corresponding Author: yjwang{at}itsa.ucsf.edu
The acute phase response (APR) is associated with down-regulation of type II nuclear hormone receptors and subsequent alterations in the expression of their target genes involved in lipid metabolism in the liver and heart. To determine whether LXR and RXR expression in kidney, particularly in metabolically active proximal tubular cells, is suppressed during the APR, we examined the expression of LXR/RXR as well as their cognate target genes in kidney from mice treated with lipopolysaccharide (LPS) and in a human proximal tubular cell line HK-2 cells treated with cytokines IL-1b and TNF-a. We found that LXRa and RXRa expression was suppressed by LPS in mouse kidney and by IL-1b or TNF-a in HK-2 cells. The decrease in LXRa/RXRa was associated with a decrease in the expression of several LXRa target genes involved in cholesterol and fatty acid metabolism (apoE, ABCA1, ABCG1 and SREBP-1c). In HK-2 cells, 22R-hydroxysterol-induced expression of apoE was also reduced by IL-1b. Moreover, IL-1b and TNF-a significantly reduced LXRE-driven transcription as measured by LXRE-linked luciferase activity. However, overexpression of LXRa/RXRa only partially restored the cytokine-mediated reduction in LXRE-linked luciferase activity. Further analysis of LXRa coactivators in HK-2 cells showed that mRNA levels of both PGC-1a and SRC-2 were decreased by IL-1b or TNF-a. Thus, these results indicate that the APR suppresses the expression of both nuclear receptors LXRa/RXRaand several LXRa coactivators in kidney. The reduction in the expression of these genes could be a mechanism for coordinate alterations in the expression of multiple LXRa target genes, which play important roles in lipid metabolism and biological functions of the kidney during the APR.
Revised on August 9, 2005
Accepted on August 9, 2005
Down-regulation of liver X receptor-
in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines
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