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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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“Meanwhile, they may also get involved in the inhibition or promotion of hepatic regeneration, inflammation, fibrosis, and neoplastic transformation, partly through the cross talk with pro-inflammatory TFs such as the nuclear factor kappa-lightchain-enhancer of activated B cells (NF-jB) [59, 60].”
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Vacca, M., Degirolamo, C., Massafra, V., Polimeno, L., Mariani‐Costantini, R., Palasciano, G., & Moschetta, A. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.025 · Cited by 49
“Furthermore, FXR displays anti-inflammatory properties by interacting with NF-jB signaling (Wang et al., 2008).”
BackgroundObeticholic acid for the treatment of nonalcoholic steatohepatitis
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“During the response to pathogenic agents, such as LPS attachment to TLR4, adaptor proteins activate signaling cascades of ubiquitination and phosphorylation in signal transducers, beginning with the recruitment of Myd88 and IRAKs, and ultimately leading to the degradation of IjB via phosphorylation of the IKK complex…”
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BackgroundEmerging role of obeticholic acid in the management of nonalcoholic fatty liver disease
Makri, E. S., Cholongitas, Ε., & Τζιόμαλος, Κ. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i41.9039 · Cited by 42
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“This is supported by observations that FXR and NFκB mutually antagonize each other [Wang et al. 2008] and activation of FXR and FGF19 inhibit the expression of NFκB controlled inflammatory genes [Drafahl et al.”
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“This may reflect an attempt of the cells to limit proinflammatory M1 macrophage activation via suppression of NF-jB signaling (Wang et al., 2008).”
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FXR protects lung from lipopolysaccharide-induced acute injury.
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“Previously, we show that FXR has antiinflammatory properties in the liver in a rodent LPS-induced inflammation model (11, 14), suggesting a role for FXR in suppressing the hepatic inflammatory response (20, 21).”
BackgroundSelf-citationCurrent Therapeutic Landscape for Metabolic Dysfunction-Associated Steatohepatitis
Devasia, A. G., Ramasamy, A., & Leo, C. H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26041778 · Cited by 45
“In terms of fibrosis reduction, FXR inhibits the transforming growth factor beta (TGF-β ) pathway, leading to decreased activation in hepatic stellate cells and collagen synthesis [267–269].”
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“Another nuclear receptor, LXR-α, has a potential role in cholesterol homeostasis, and the ligand-dependent activation of LXR-α has an anti-inflammatory effect through repressing NF-ҡB-mediated signaling (Wu et al., 2009; Endo-Umeda and Makishima, 2019).”
BackgroundInfluentialThe role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD
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“…serum BA levels may also explain, in part, the higher acute phase protein concentrations in CMP versus control cows after calving, because lower BA concentrations may result via less farnesoid X receptor activation in more proinflammatory cytokine synthesis and inflammation (Wang et al., 2008).”
BackgroundThe intestinal microbiome and paediatric liver disease
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Nuclear factor-κB regulates the expression of multiple genes encoding liver transport proteins.
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“This activation of NF-κ B may stem from oxidant release due to ER-mediated stress, NF-κB then prompts the induction of NLRP3, leading to the assembly with ASC and procaspase-1. leading to the dissociation of TXNIP from Trx and subsequent binding and activation of NF-κ B. NF-κ B This leads to caspase-1-mediated convers…”
InfluentialBile acid and nonalcoholic steatohepatitis: Molecular insights and therapeutic targets
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“FXR is also an important inhibitor of hepatic inflammation, as evident by the spontaneous liver injury, inflammation and increased sensitivity to NF-kB activation seen in FXRdeficient mice (Figure 1) [46].”
BackgroundYe, M., Fan, M., Zhao, Y., Wang, F., Yang, X., Yao, W., Gao, X., Yu, J., & Liu, W. (2025) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2025.124050 · Cited by 35
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“Pharmacologic FXR agonists have beneficial anti-inflammatory, anti-cholestatic and anti-fibrotic effects on the liver; as well as beneficial effects on glucose and lipid metabolism.((45,46)) Our data demonstrate that FXR agonists may also be hepatoprotective due to an interaction with the IRE1a/XBP1 pathway.”
BackgroundMechanisms of STAT3 activation in the liver of FXR knockout mice
Li, G., Zhu, Y., Tawfik, O. W., Kong, B., Williams, J. A. R., Zhan, L., Kassel, K. M., Luyendyk, J. P., Wang, L., & Guo, G. L. (2013) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00155.2013 · Cited by 36
Bacterial metabolites directly modulate farnesoid X receptor activity
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“Recent evidence showed that FXR activation is critical in the regulation of inflammatory responses [9–11].”
BackgroundGut microbiota in MAFLD: therapeutic and diagnostic implications
Alghamdi, W., Mosli, M. H., & Alqahtani, S. A. (2024) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188241242937 · Cited by 33
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“As a recognized BA receptor, farnesoid X receptor (FXR) (also called NR1H4) functions as a ligand-regulated transcription factor that mediates the expression of different genes involved in cholesterol/BA metabolism, liver gluconeogenesis, and lipogenesis [11].”
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Post-Translational Modifications of FXR; Implications for Cholestasis and Obesity-Related Disorders
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“Besides transactivation, FXR can also downregulate transcription via transrepression, by for example binding to nuclear factor kappa B (NF-kB), thereby prohibiting NF-kB-mediated (26, 39).”
BackgroundTargeting Nuclear Receptors for Cancer Therapy: Premises, Promises, and Challenges
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“Nevertheless, activating the FXR selectively inhibits a hepatic inflammatory reaction mediated by NF-κB and impairs the aggregation of macrophages into body tissues by downregulating monocyte chemoattractant protein-1 (MCP-1) levels (Wang et al., 2008; Li et al., 2015).”
BackgroundFXR-Deoxycholic Acid-TNFα Axis Modulates Acetaminophen-Induced Hepatotoxicity.
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“It also has been demonstrated that the activation of FXR repressed specific sets of NF‑ κ B target genes in response to the NF-κ B activators (LPS and TNF-α ) (29).”
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“, COX-2 and inducible nitric oxide synthase) genes (132).”
BackgroundSynthetic FXR Agonist GW4064 Is a Modulator of Multiple G Protein–Coupled Receptors
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“Induction of cell death in MCF-7 and HEK cells by GW4064 is FXR independent GW4064 has been reported to promote apoptosis of colon cancer and breast cancer (MCF-7) cells (11, 12, 23, 28), whereas in HepG2 hepatoma cells, it protects against serum deprivation–induced apoptosis (11, 25).”
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“Human hepatoblastoma cells (HepG2) were seeded into 6-well plates (1 × 106 cells/well) and grown in complete culture medium [high-glucose Dulbecco’s modified Eagle’s medium (with L-glutamine) supplied with 10% (vol/vol) inactivated fetal calf serum and 1% (vol/vol) antibiotics–antimycotics] as described [38].”
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“…factors such as nuclear factor-κ B (NF-κ B). transcription by transcription factors such as nuclear factor-κ B (NF-κ B). mice exhibit severe hepatic inflammation and spontaneous liver tumors [44]. et FXR-knockout mice exhibit severe hepatic in fl ammation and spontaneous liver tumors [44].”
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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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