Abstract
BACKGROUND/AIMS: A recently determined target of lipopolysaccharide (LPS) and cytokine signaling in liver is the central Type II nuclear receptor (NR) heterodimer partner, retinoid X receptor alpha (RXRalpha). We sought to determine if Rosiglitazone (Rosi), a peroxisome proliferator activated receptor gamma (PPARgamma) agonist with anti-inflammatory properties, can attenuate LPS and cytokine-induced molecular suppression of RXRalpha-regulated genes. METHODS: In vivo, mice were gavage-fed Rosi for 3 days, prior to intraperitoneal injection of LPS, followed by harvest of liver and serum. In vitro, HepG2 cells were treated with IL-1beta, +/- short-term Rosi pretreatment. RNA was analyzed by quantitative RT-PCR, while nuclear and cytoplasmic proteins were analyzed by immunoblotting and gel shifts. RESULTS: Rosi attenuated LPS-mediated suppression of RNA levels of several Type II NR-regulated genes, including bile acid transporters and the major drug metabolizing enzyme, Cyp3a11, without affecting cytokine expression, suggesting a novel, direct anti-inflammatory effect in hepatocytes. Rosi suppressed the inflammation-induced nuclear export of RXRalpha, in both LPS-injected mice and IL-1beta-treated HepG2 cells, leading to maintenance of nuclear RXRalpha levels and heterodimer binding activity. CONCLUSIONS: Rosi directly attenuates the suppressive effects of inflammation-induced cell signaling on nuclear RXRalpha levels in liver.