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

The acute phase response (APR) is associated with decreased hepatic expression of many proteins involved in lipid metabolism. The nuclear hormone receptors peroxisome proliferator-activated receptor alpha (PPAR alpha) and liver X receptor (LXR) play key roles in regulation of hepatic lipid metabolism. Because heterodimerization with RXR is crucial for their action, we hypothesized that a decrease in RXR may be one mechanism to coordinately down-regulate 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%). These decreases were associated with a marked reduction in RXR alpha, RXR beta, and RXR gamma mRNA levels. Increased RNA degradation is likely responsible for the repression of RXR, because LPS did not decrease RXR beta and RXR gamma transcription and only marginally inhibited (38%) RXR alpha transcription. RXR repression was associated with decreased LXR alpha and PPAR alpha mRNA levels and reduced RXR.RXR, RXR.PPAR and RXR.LXR binding activities in nuclear extracts. Furthermore, LPS markedly decreased both basal and Wy-14,643-induced expression of acyl-CoA synthetase, a well characterized PPAR alpha target. The reduction in hepatic RXR levels alone or in association with other nuclear hormone receptors could be a mechanism for coordinately inhibiting the expression of multiple genes during the APR.