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标题：Downregulation of liver X receptor-{alpha} in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines
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作者：Wang, Yuwei ; Moser, Arthur H. ; Shigenaga, Judy K. 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2005
卷号：46
期号：11
页码：2377-2387
DOI：10.1194/jlr.M500134-JLR200
出版社：American Society for Biochemistry and Molecular Biology
摘要：The acute-phase response (APR) suppresses type II nuclear hormonereceptors and alters the expression of their target genes involvedin lipid metabolism in the liver and heart. Therefore, we examinedthe 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 withinterleukin-1ß (IL-1ß) and tumor necrosisfactor- ${alpha}$ (TNF- ${alpha}$ ). We found that LXR ${alpha}$ and RXR ${alpha}$ expression was suppressedby LPS in kidney and by IL-1ß or TNF- ${alpha}$ in HK-2 cells.The decrease in LXR ${alpha}$ /RXR ${alpha}$ expression was associated with a decreasein the expression of several LXR ${alpha}$ target genes [apolipoproteinE (apoE), ABCA1, ABCG1, and sterol-regulatory element bindingprotein-1c (SREBP-1c)] and a decrease in ligand-induced apoEexpression. Moreover, IL-1ß and TNF- ${alpha}$ significantlyreduced liver X receptor response element (LXRE)-driven transcriptionas measured by LXRE-linked luciferase activity. However, overexpressionof LXR ${alpha}$ /RXR ${alpha}$ only partially restored the cytokine-mediated reductionin LXRE-linked luciferase activity. Additionally, expressionof the LXR coactivators peroxisome proliferator-activated receptor ${gamma}$ coactivator 1 ${alpha}$ (PGC1 ${alpha}$ ) and steroid receptor coactivator-2 (SRC-2)was decreased by IL-1ß or TNF- ${alpha}$ . We conclude that the APR suppresses the expression of both nuclearreceptors LXR ${alpha}$ /RXR ${alpha}$ and several LXR ${alpha}$ coactivators in kidney, whichcould be a mechanism for coordinately regulating the expressionof multiple LXR target genes that play important roles in lipidmetabolism 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 ${gamma}$ 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