Rosiglitazone attenuates suppression of RXRα-dependent gene expression in inflamed liver

Background/AimsA recently determined target of lipopolysaccharide (LPS) and cytokine signaling in liver is the central Type II nuclear receptor (NR) heterodimer partner, retinoid X receptor α (RXRα). We sought to determine if Rosiglitazone (Rosi), a peroxisome proliferator activated receptor γ (PPARγ) agonist with anti-inflammatory properties, can attenuate LPS and cytokine-induced molecular suppression of RXRα-regulated genes.MethodsIn 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-1β, ± short-term Rosi pretreatment. RNA was analyzed by quantitative RT-PCR, while nuclear and cytoplasmic proteins were analyzed by immunoblotting and gel shifts.ResultsRosi 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 RXRα, in both LPS-injected mice and IL-1β-treated HepG2 cells, leading to maintenance of nuclear RXRα levels and heterodimer binding activity.ConclusionsRosi directly attenuates the suppressive effects of inflammation-induced cell signaling on nuclear RXRα levels in liver.