The acute phase response is associated with retinoid X receptor repressionin rodent liver

The acute phase response (APR) is associated with decreased hepatic express ion of many proteins involved in lipid metabolism. The nuclear hormone rece ptors peroxisome proliferator-activated receptor alpha (PPAR alpha) and liv er X receptor (LXR) play key roles in regulation of hepatic lipid metabolis m. Because heterodimerization with RXR is crucial for their action, we hypo thesized that a decrease in RXR may be one mechanism to coordinately down-r egulate gene expression during APR. We demonstrate that lipopolysaccharide (LPS) induces a rapid, dose-dependent decrease in RXR alpha, RXR beta, and RXR gamma proteins in hamster liver. Maximum inhibition was observed at 4 h for RXR alpha (62%) and RXR beta (50%) and at 2 h for RXR gamma (61%). The se decreases were associated with a marked reduction in RXR alpha, RXR beta , and RXR gamma mRNA levels. Increased RNA degradation is likely responsibl e for the repression of RXR, because LPS did not decrease RXR beta and RXR gamma transcription and only marginally inhibited (38%) RXR alpha transcrip tion. RXR repression was associated with decreased LXR alpha and PPAR alpha mRNA levels and reduced RXR.RXR, RXR.PPAR and RXR.LXR binding activities i n nuclear extracts. Furthermore, LPS markedly decreased both basal and Wy-1 4,643-induced expression of acyl-CoA synthetase, a well characterized PPAR alpha target. The reduction in hepatic RXR levels alone or in association w ith other nuclear hormone receptors could be a mechanism for coordinately i nhibiting the expression of multiple genes during the APR.