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

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 tar- get genes in kidney from mice treated with lipopolysac- charide (LPS) and in human proximal tubular HK-2 cells treated with interleukin-1 � (IL-1 � ) and tumor necrosis fac- tor- � (TNF- � ). We found that LXRand RXRexpression was suppressed by LPS in kidney and by IL-1 � or TNF- � in HK-2 cells. The decrease in LXR � /RXRexpression 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-1 � and TNF- � significantly reduced liver X receptor response element (LXRE)-driven transcription as measured by LXRE-linked luciferase activity. However, overexpression of LXR � /RXRonly partially restored the cytokine-mediated reduction in LXRE-linked luciferase activity. Additionally, expression of the LXR coactivators per- oxisome proliferator-activated receptorcoactivator 1 � (PGC1 � ) and steroid receptor coactivator-2 (SRC-2) was decreased by IL-1 � or TNF- � . We conclude that the APR suppresses the expression of both nuclear receptors LXR � / RXRand several LXRcoactivators in kidney, which could be a mechanism for coordinately regulating the ex- pression of multiple LXR target genes that play important roles in lipid metabolism in kidney during the APR. —Wang, Y., A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Fein- gold. Downregulation of liver X receptor- � in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines. J. Lipid Res. 2005. 46: 2377-2387.