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

Journal of Lipid Research

Carl Grunfeld¹  Yuwei Wang¹  Arthur H. Moser¹  Judy K. Shigenaga¹  Kenneth R. Feingold² 

[1] Department of Medicine, University of California San Francisco, and Metabolism Section, Department of Veterans Affairs Medical Center, San Francisco, CA 94121;To whom correspondence should be addressed.;

关键词: lipopolysaccharide;    acute-phase response;    lipid metabolism;   

DOI  :  

来源: DOAJ

【 摘 要 】

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-1β (IL-1β) and tumor necrosis factor-α (TNF-α). We found that LXRα and RXRα expression was suppressed by LPS in kidney and by IL-1β or TNF-α in HK-2 cells. The decrease in LXRα/RXRα expression was associated with a decrease in the expression of several LXRα 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-1β and TNF-α significantly reduced liver X receptor response element (LXRE)-driven transcription as measured by LXRE-linked luciferase activity. However, overexpression of LXRα/RXRα only partially restored the cytokine-mediated reduction in LXRE-linked luciferase activity. Additionally, expression of the LXR coactivators peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and steroid receptor coactivator-2 (SRC-2) was decreased by IL-1β or TNF-α.We conclude that the APR suppresses the expression of both nuclear receptors LXRα/RXRα and several LXRα 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.

【 授权许可】

Unknown