Tumor necrosis factor and interleukin 1 decrease RXRα, PPARα, PPARγ, LXRα, and the coactivators SRC-1, PGC-1α, and PGC-1β in liver cells

During the acute phase response, cytokines induce marked alterations in lipid metabolism including an increase in serum triglyceride levels and a decrease in hepatic fatty acid oxidation, in bile acid synthesis, and in high-density lipoprotein levels. Here we demonstrate that tumor necrosis factor (TNF) and interleukin 1 (IL-1), but not IL-6, decrease the expression of retinoid X receptor alpha (RXR alpha), peroxisome proliferator-activated receptor alpha (PPAR alpha), PPAR gamma, liver X receptor alpha (LXR alpha), and coactivators PPAR gamma coactivator 1 alpha (PGC-1 alpha), PGC-1 beta, and steroid receptor coactivator 1 (SRC-1) in Hep3B human hepatoma cells. In addition, treatment of mice with TNF and IL-1 also decreased RXR alpha, PPAR alpha, PPAR gamma, LXR alpha, and PGC-1 alpha messenger RNA (mRNA) levels in the liver. These decreases were accompanied by reduced binding of nuclear extracts to RXR, PPAR, and LXR response elements and decreased luciferase activity driven by PPAR and LXR response elements. In addition, the mRNA levels of proteins regulated by PPAR alpha (carnitine palmitoyltransferase 1 alpha) and LXR (sterol regulatory element binding protein) were decreased in Hep3B cells treated with TNF or IL-1. Finally, using constructs of the LXR alpha promoter or the PGC-1 alpha promoter linked to luciferase, we were able to demonstrate that a decrease in transcription contributes to the reduction in mRNA levels of nuclear hormone receptors and coactivators. Thus, our results suggest that decreased expression of nuclear hormone receptors RXR alpha, PPAR alpha, PPAR gamma, and LXR alpha, as well as coactivators PGC-1 alpha, PGC-1 beta, and SRC-1 may contribute to the cytokine-induced alterations in hepatic lipid metabolism during the acute phase response. (c) 2007 Elsevier Inc. All rights reserved.