Reply

Abstract

We agree with the commentary by Drs Chignard and Poupon, particularly with respect to the point that FXR activation suppresses inducible nitric oxide synthase (iNOS) mRNA level induced by lipopolysaccharide (LPS) probably in an nuclear factor (NF)-κB–independent manner. LPS activates not only NF-κB, but also other transcriptional factors, such as AP-1. iNOS is a target gene of both NF-κB and AP-1, so it is possible that FXR activation may suppress iNOS expression induced by LPS in an AP-1 dependent manner. It is known that several nuclear receptors such as GR, PPAR-γ, and LXR can antagonize the activity of NF-κB (Genes Dev 2000;14:2314–2329; Nature 2005;437:759–763; Mol Cell 2007;25:57–70). Our study expands it by adding FXR to this list. In addition, nuclear receptors antagonize NF-κB signaling through different mechanisms (Genes Dev 2000;14:2314–2329; Nature 2005;437:759–763; Mol Cell 2007;25:57–70). Our study (Hepatology 2008;48:1632–1643) indicates that FXR does not affect p65 nuclear translocation but suppresses p65 transactivity by decreasing its DNA binding. It would be interesting to further determine by which mechanism FXR suppresses NF-κB signaling in the future research work. Drs Chignard and Poupon highlight FXR agonists as a potential therapy tools for inflammatory biliary diseases. We would like to point out that they did not mention another critical role of FXR in liver regeneration (Science 2006;312:233–236), which constitutes another level of defense mechanism by which FXR can suppress liver inflammation. Recent studies have indicated that impaired liver regeneration may lead to continuing cell death, which results in chronic inflammation in the liver. Several components released from dead cells are known to activate Kupffer cells (liver resident macrophages) and other cells to induce the expression of proinflammatory cytokines (Cell Res 2008;18:334–342; Science 2009;323:1722–1725). In summary, FXR is a novel cell protector that not only controls the bile acid levels but also directly participates in several cellular defense pathways (Cell Res 2008;18:1087–1095). Finally, our other studies also suggest that FXR agonist ligands offer possible therapies for other liver diseases such as fibrosis and hepatocellular carcinoma (Cancer Res 2007;67:863–867). Hopefully, in the near future, FXR agonists can be developed into drugs for clinical treatment of different liver diseases. Targeting Farnesoid X Receptor in Hepatic and Biliary Inflammatory DiseasesGastroenterologyVol. 137Issue 2PreviewWang YD, Chen WD, Wang M, et al. (Department of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, Duarte, California). Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008;48:1632–1643. Full-Text PDF