Inflammation and proinflammatory
cytokines suppress the expression of several hepatic transporters and metabolic
enzymes, often resulting in cholestatic
liver disease. However, mechanism(s) of this down-regulation have not been fully elucidated. As the
pregnane X receptor (PXR) is involved in inducing many of these hepatic
proteins, it is possible that PXR is also involved in their down-regulation during
inflammation. Thus, we compared the effect of
inflammation on hepatic gene regulation in wild-type (PXR(+/+)) versus PXR-null (PXR(-/-)) mice. Treatment of PXR(+/+) but not PXR(-/-) mice with the PXR activators 5-pregnen-3beta-ol-20-one-16alpha-carbonitrile (
PCN) or 17beta-hydroxy-11beta-[4-dimethylamino phenyl]-17alpha-[1-propynyl] estra-4,9-dien-3-one (
RU486) resulted in increased
mRNA levels of bsep, mdr1a, mrp2, mrp3, oatp2, and cyp3a11, indicating involvement of PXR in their regulation. Significantly lower
mRNA levels of bsep, mdr2, mrp2, mrp3, ntcp, oatp2, and cyp3a11 were found in
endotoxin-treated PXR(+/+) mice. In
endotoxin-treated PXR(-/-) mice, the extent of mrp2 suppression was significantly diminished. Changes in MRP2 expression were supported by Western blot analysis. Although
interleukin (IL)-6 imposed significant decreases in the expression of bsep, mrp2, and cyp3a11 in PXR(+/+) mice, this was not observed in PXR(-/-) mice. Of note, significantly lower levels of PXR
mRNA and
protein were detected in
endotoxin- and IL-6-treated PXR(+/+) mice. In addition,
endotoxin and
IL-6 were also able to suppress
PCN-mediated induction of bsep, mrp2, cyp3a11, and PXR. Taken together, our results suggest that PXR plays a role in the down-regulation of several hepatic
proteins during
inflammation.