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

Abstract

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. Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc.