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Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response
Open accessAbstract
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.)
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In the citing paper
“FXR agonists are known to alleviate endoplasmic reticulum stress and suppress oxidative damage by upregulating antioxidant and anti-apoptotic pathways [42, 43].”
From High-throughput human microfluidic organoid-on-a-chip platform for modeling liver diseases and screening nanotherapeutics. (2026) · cites this paper as [43]
Experimental — accuracy not yet measuredIn the citing paper
“Ablation of Nr1h4 (hereafter referred to as Fxr) not only promotes cholestasis but also NAFLD, NASH and HCC in mice (Kim et al., 2007; Lu et al., 2000; Wang et al., 2008; Watanabe et al., 2004; Yang et al., 2007).”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Wang et al., 2008
In the citing paper
“Next to their extensive effect on cell metabolism, they are able to mediate anti-inflammatory effects through direct interaction with other transcription factors, such as NF-κB or activator protein-1 (AP-1) [26,27], and even repress proinflammatory gene expression by interfering with TLR signaling.[28]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [27]
In the citing paper
“In brief, FXR interacts with NF-κB signaling and inhibits pro-inflammatory genes (e.g., TNF-α, inducible nitric oxide synthase (iNOS), Cyclooxygeanse-2 (COX-2), CCL-2 and IL-1β)), while NF-κB activation reciprocally antagonizes FXR activity.[27,52,53]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [27]
In the citing paper
“Additionally, FXR -/-mice were more susceptible to inflammatory stress, highlighting the anti- inflammatory properties of FXR.[27]”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [27]
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Metadata
- Authors
- Wang, Y.-D., Chen, W.-D., Wang, M., Yu, D., Forman, B. M., & Huang, W.
- Affiliations
- City Of Hope National Medical Center (US)
- Corresponding author
- Huang, Wendong
- Venue
- Hepatology
- Published
- 2008-11
- Volume
- 48
- Issue
- 5
- Pages
- 1632-1643
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC3056574
- OpenAlex
- W2021998283
- Cited by
- 639
- References
- 52
- Citations by year
- 2026: 30 · 2025: 46 · 2024: 44 · 2023: 46 · 2022: 51 · 2021: 54 · 2020: 45 · 2019: 42 · 2018: 31 · 2017: 42 · 2016: 38 · 2015: 29 · 2014: 31 · 2013: 27 · 2012: 27
- FWCI
- 9.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Sidney Kimmel Foundation for Cancer Research
- Sidney Kimmel Foundation
- National Cancer Institute (P30CA033572)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- farnesoid X receptor, nuclear factor-kappaB, liver inflammation, hepatoprotection, lipopolysaccharide, inducible nitric oxide synthase, cyclooxygenase-2, CXCL10, interferon-gamma, liver necrosis, hepatocarcinogenesis, anti-apoptotic genes
- MeSH terms
- Receptor, Farnesoid X-Activated, Animals, Cell Line, DNA-Binding Proteins, Homeostasis, Humans, Inflammation, Kidney, Liver, Liver Neoplasms, Necrosis, RNA, Messenger, Transcription Factors, Tumor Necrosis Factor-alpha, NF-kappa B, Receptors, Cytoplasmic and Nuclear, Hepatoblastoma, Mice, Knockout, Cell Line, Tumor, Mice, Cyclooxygenase 2, Nitric Oxide Synthase Type II
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