GENES: STRUCTURE AND REGULATION
The Acute Phase Response Is Associated with Retinoid X Receptor Repression in Rodent Liver*

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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 α (PPARα) 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 RXRα, RXRβ, and RXRγ proteins in hamster liver. Maximum inhibition was observed at 4 h for RXRα (62%) and RXRβ (50%) and at 2 h for RXRγ (61%). These decreases were associated with a marked reduction in RXRα, RXRβ, and RXRγ mRNA levels. Increased RNA degradation is likely responsible for the repression of RXR, because LPS did not decreaseRXRβ and RXRγ transcription and only marginally inhibited (38%) RXRα transcription. RXR repression was associated with decreased LXRα and PPARα 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 PPARα 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.

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Published, JBC Papers in Press, March 21, 2000, DOI 10.1074/jbc.M000953200

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This work was supported by grants from the Research Service of the Department of Veterans Affairs and by National Institutes of Health Grants DK 49448 and AR 39639.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.