Acute systemic lipopolysaccharide (endotoxin, LPS) exposure, which can lead to septic shock, enhances the hepatic expression of inflammatory and acute-phase proteins (APPs). To better understand how LPS aggravates damage, changes in hepatic gene expression after a single LPS dose was screened by using microarrays for 1176 rat genes. We detected more than 20 new potential LPS-induced APPs. Following acute LPS challenge, significant up-regulation of the steady-state mRNA levels of several important early transcription factors, such as c-jun and STAT3, and cytokine-associated genes, was observed. In contrast, RT-PCR analysis revealed marked down-regulation of the nuclear receptors RXRalpha, PXR, FXR, LXR, PPARalpha and CAR. Also genes encoding lipolytic, antioxidant as well as drug- and alcohol-metabolizing enzymes were down-regulated. These data suggest that acute LPS treatment induces important early transcription factors and co-ordinately down-regulates nuclear receptors, and that this results in altered expression of a large number of downstream genes.