Farnesoid X receptor antagonizes NF-κB in hepatic inflammatory response
By Yan-Dong Wang, Wei-Dong Chen, Meihua Wang, Donna D. Yu, B. M. Forman, Wendong Huang. Hepatology, 2008
600 citations recorded by the source corpus.
The farnesoid X receptor (FXR) is a nuclear receptor that plays key roles in hepatoprotection by maintaining the homeostasis of liver metabolism. FXR null mice display strong hepatic inflammation and develop spontaneous liver tumors. In this report, we demonstrate that FXR is a negative modulator of nuclear factor κB (NF‐κB)–mediated hepatic inflammation. Activation of FXR by its agonist ligands inhibited the expression of inflammatory mediators in response to NF‐κB activation in both HepG2 cells and primary hepatocytes cultured in vitro. In vivo, compared with wild‐type controls, FXR−/− mice displayed elevated messenger RNA (mRNA) levels of inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), interferon‐inducible protein 10, and interferon‐γ in response to lipopolysaccharide (LPS). Examination of FXR−/− livers showed massive necroses and inflammation after treatment with LPS at a dose that does not induce significant liver damage or inflammation in wild‐type mice. Moreover, transfection of a constitutively active FXR expression construct repressed the iNOS, COX‐2, interferon‐inducible protein 10 and interferon‐γ mRNA levels induced by LPS administration. FXR activation had no negative effects on NF‐κB‐activated antiapoptotic genes, suggesting that FXR selectively inhibits the NF‐κB‐mediated hepatic inflammatory response but maintains or even enhances the cell survival response. On the other hand, NF‐κB activation suppressed FXR‐mediated gene expression both in vitro and in vivo, indicating a negative crosstalk between the FXR and NF‐κB signaling pathways. Our findings reveal that FXR is a negative mediator of hepatic inflammation, which may contribute to the critical roles of FXR in hepatoprotection and suppression of hepatocarcinogenesis. (HEPATOLOGY 2008;48:1632–1643.)
Subfields: Cancer Research, Oncology, Pharmacology
View Paper: https://www.semanticscholar.org/paper/1188a6458419ee4d7fdf40eafbd37632f6e77762
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In Oncology
Citations in the corpus
- Hepatic inflammatory responses in liver fibrosis (2023, unknown): “By contrast, activation of the nuclear receptor farnesoid X receptor (FXR) in hepatocytes by distinct (endogenous or synthetic) bile acids prevents the upregulation of inflammatory response genes and promotes cell survival 34 .”
- Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME (2013, unknown): “Stimulation of FXR in isolated hepatocytes and HepG2 hepatoma cells significantly suppressed NF-kappaB transcriptional activity (Wang et al. 2008a).”
- Bile Acid Signaling in Metabolic Disease and Drug Therapy (2014, background): “OCA antagonizes NF-kB–stimulated inflammation in liver (Wang et al., 2008), modulates innate immunity in animal models of colitis (Vavassori et al.”