The Involvement of the Pregnane X Receptor in Hepatic Gene Regulation during Inflammation in Mice

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