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The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis
Open accessAbstract
Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR(-/-) mice are more susceptible to Con A-induced hepatitis and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production. These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.
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“the inflammatory effects of BAR deficiency on the liver may not only be mediated by Kupffer cells, but also by hepatocytes and NKT cells (Mencarelli et al., 2009; Y.-D. Wang et al., 2008).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Mencarelli et al., 2009
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“Liver lipidomic analyses were performed by gas chromatography for triglyceride, FC, and cholesteryl ester (CE) and by high-performance liquid chromatography for total FAs (30).”
BackgroundInfluentialInflammation and Fibrogenesis in MAFLD: Role of the Hepatic Immune System
Torre, P., Motta, B. M., Sciorio, R., Masarone, M., & Persico, M. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.781567 · Cited by 49
“Bile acids and the extracellular matrix (as described below) can also modulate the immune response in the liver (19, 42, 43).”
BackgroundGut Microbiome and Common Variable Immunodeficiency: Few Certainties and Many Outstanding Questions
Varricchi, G., Poto, R., Ianiro, G., Punziano, A., Marone, G., Gasbarrini, A., & Spadaro, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.712915 · Cited by 45
FXR protects lung from lipopolysaccharide-induced acute injury.
Zhang, L.-S., Li, T., Yu, D. D., Forman, B. M., & Huang, W.-D. (2012) · Molecular Endocrinology · doi:10.1210/me.2011-0042 · Cited by 39
“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).”
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
Traussnigg, S., Halilbasic, E., Hofer, H., Munda, P., Stojaković, T., Fauler, G., Kashofer, K., Krššák, M., Wolzt, M., & Trauner, M. (2020) · Wiener klinische Wochenschrift · doi:10.1007/s00508-020-01735-5 · Cited by 42
Gut bacteria Prevotellaceae related lithocholic acid metabolism promotes colonic inflammation
Chen, L.-P., Ye, Z.-H., Li, J.-H., Wang, L., Chen, Y., Yu, M., Han, J., Huang, J., Li, D.-Y., Lv, Y., et al. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-024-05873-6 · Cited by 43
“One potential mechanism could involve the perturbation of cell membranes, subsequently activating protein kinase C and releasing arachidonic acid [36], which stimulated the production of inflammatory factors such as TNF-α [37, 38].”
Carino, A., Biagioli, M., Marchianò, S., Scarpelli, P., Zampella, A., Limongelli, V., & Fiorucci, S. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.02.033 · Cited by 42
“4A–B exposure to CCl4 resulted in a robust induction of the expression of signature cytokines including Tnfα, Il1β, Ifnγ, Mcp1 and Il6 in the liver [37].”
BackgroundMicrobiome modulates intestinal homeostasis against inflammatory diseases
Sun, X., & Jia, Z. (2018) · Veterinary Immunology and Immunopathology · doi:10.1016/j.vetimm.2018.10.014 · Cited by 44
Halilbasic, E., Fuchs, C. D., Traussnigg, S., & Trauner, M. (2016) · Digestive Diseases · doi:10.1159/000445268 · Cited by 39
Carino, A., Marchianò, S., Biagioli, M., Fiorucci, C., Zampella, A., Monti, M. C., Morretta, E., Bordoni, M., Giorgio, C. D., Roselli, R., et al. (2019) · Nutrients · doi:10.3390/nu11051132 · Cited by 38
“Additionally, FXR activation regulates liver innate immunity [3,6,18], reduces lipogenesis, and promotes fatty acid β-oxidation [18], thereby protecting against hepatic steatosis.”
BackgroundThe farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion
Hucke, S., Herold, M. V. B., Liebmann, M., Freise, N., Lindner, M., Fleck, A.-K., Zenker, S., Thiebes, S., Fernández‐Orth, J., Buck, D., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1593-6 · Cited by 39
“Such lack of a phenotype in FXR mice has also been observed in animal models of chemically-induced colitis [15, 54], whereas FXR mice show aggravation of inflammation in the context of hepatitis [38].”
BackgroundObeticholic Acid and Other Farnesoid-X-Receptor (FXR) Agonists in the Treatment of Liver Disorders
Fiorucci, S., Urbani, G., Distrutti, E., & Biagioli, M. (2025) · Pharmaceuticals · doi:10.3390/ph18091424 · Cited by 42
Guo, S., Peng, Y., Lou, Y., Cao, L., Liu, J., Lin, N., Cai, S., Kang, Y., Zeng, S., & Yu, L. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106101 · Cited by 36
Jin, D., Lu, T.-F., Ni, M., Wang, H., Zhang, J., Zhong, C., Shen, C., Hao, J.-F., Busuttil, R., Kupiec-Weglinski, J., et al. (2020) · Hepatology Communications · doi:10.1002/hep4.1478 · Cited by 29
“(32) FXR-deficient mice have been shown to develop much worse liver necrosis and more severe inflammation after treatment with LPS(32) or concanavalin A (ConA),(33) and FXR agonists reduce not only acute inflammatory hepatocellular damage(34) but also inflammatory cell infiltration and hepatic fibrosis/steatosis(35-37…”
BackgroundCaffaratti, C., Plazy, C., Méry, G., Tidjani, A.-R., Fiorini, F., Thiroux, S., Toussaint, B., Hannani, D., & Gouëllec, A. L. (2021) · Metabolites · doi:10.3390/metabo11060406 · Cited by 36
Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa
Distrutti, E., Santucci, L., Cipriani, S., Renga, B., Schiaroli, E., Ricci, P., Donini, A., & Fiorucci, S. (2015) · Journal of Gastroenterology · doi:10.1007/s00535-015-1041-8 · Cited by 33
“Importantly, FXR-deficient mice display a severe alteration in bile acid and phospholipid homeostasis [42].”
BackgroundInfluentialBiagioli, M., & Fiorucci, S. (2021) · Liver Research · doi:10.1016/j.livres.2021.08.003 · Cited by 33
“6,254,257,258,342,344,355,368 Consistent with this view, mice de fi cient for FXR or GPBAR1 are more prone than their wild-type counterparts to develop in fl ammation with age and react to challenges with pro-in fl ammatory agents with an exaggerated generation of in fl ammatory mediators.”
Gut microbiota: A double-edged sword in immune checkpoint blockade immunotherapy against tumors
Wang, J., Zhu, N., Su, L., & Yang, R. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216582 · Cited by 35
Liu, R., Wang, J., Liu, Y., Gao, Y., & Yang, R. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217115 · Cited by 33
Zheng, Y., Sun, W., Wang, Z., Liu, J., Shan, C., He, C., Li, B., Hu, X., Zhu, W., Liu, L., et al. (2022) · Research · doi:10.34133/2022/9784081 · Cited by 34
“FXR promoted the transactivation of SHP to inhibit c-Jun-mediated osteopontin production in NKT cells and mitigated acute hepatitis (15).”
BackgroundFiorucci, S., Biagioli, M., Baldoni, M., Ricci, P., Sepe, V., Zampella, A., & Distrutti, E. (2021) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2021.1916465 · Cited by 30
Pleiotropic roles of FXR in liver and colorectal cancers
Huang, X., Fan, M., & Huang, W. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111543 · Cited by 32
Potential therapeutic strategies for MASH: from preclinical to clinical development
Xie, Z., Li, Y., Cheng, L., Huang, Y., Rao, W., Shi, H., & Li, J. (2024) · Life Metabolism · doi:10.1093/lifemeta/loae029 · Cited by 31
FXR Agonists: From Bench to Bedside, a Guide for Clinicians
Alawad, A., & Levy, C. (2016) · Digestive Diseases and Sciences · doi:10.1007/s10620-016-4334-8 · Cited by 25
“These findings were corroborated by another study reporting that FXR-/- mice were more susceptible to concanavalin A-induced T cell hepatitis, and administering OCA to wild-type mice attenuated concanavalin A-induced liver injury [36].”
ResultStimulation of the farnesoid X receptor promotes M2 macrophage polarization
Jaroonwitchawan, T., Arimochi, H., Sasaki, Y., Ishifune, C., Kondo, H., Otsuka, K., Tsukumo, S., & Yasutomo, K. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1065790 · Cited by 31
“For instance, FXR-deficient mice were shown to develop more severe liver inflammation, after administration of LPS or Con A-induced hepatitis (15, 16).”
BackgroundAleti, G., Troyer, E. A., & Hong, S. (2023) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2023.100671 · Cited by 30
Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice
Meng, Z.-P., Wang, X.-Q., Gan, Y., Zhang, Y., Zhou, H., van Ness, C., Wu, J., Lou, G., Yu, H., He, C., et al. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.06.016 · Cited by 26
Bessonneau, V., Gerona, R. R. L., Trowbridge, J., Grashow, R. G., Lin, T. S., Buren, H., Morello-Frosch, R. A., & Rudel, R. A. (2021) · Scientific Reports · doi:10.1038/s41598-021-87070-9 · Cited by 30
Bile acids and their receptors in hepatic immunity
Fiorucci, S., Marchianò, S., Distrutti, E., & Biagioli, M. (2025) · Liver Research · doi:10.1016/j.livres.2025.01.005 · Cited by 31
“56 e 58 In the immune system, FXR expression is largely restricted to myeloid cells, 59 including monocytes, macrophages, DCs, and nat-ural killer (NK) cells.”
Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis
Ding, C., Wang, Z., Dou, X., Yang, Q., Ning, Y., Kao, S., Sang, X., Hao, M., Wang, K., Peng, M., et al. (2023) · Aging and Disease · doi:10.14336/ad.2023.0830 · Cited by 29
Microbial metabolites and immunotherapy: Basic rationale and clinical indications
Kovtonyuk, L. V., & McCoy, K. D. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101755 · Cited by 25
Urbani, G., Rondini, E., Distrutti, E., Marchianò, S., Biagioli, M., & Fiorucci, S. (2025) · Cells · doi:10.3390/cells14080595 · Cited by 28
Metadata
- Authors
- Mencarelli, A., Renga, B., Migliorati, M., Cipriani, S., Distrutti, E., Santucci, L., & Fiorucci, S.
- Affiliations
- University of Perugia (IT)
- Azienda Ospedaliera di Perugia (IT)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-11
- Volume
- 183
- Issue
- 10
- Pages
- 6657-6666
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2101271723
- Cited by
- 177
- References
- 66
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 11 · 2023: 21 · 2022: 21 · 2021: 19 · 2020: 6 · 2019: 9 · 2018: 5 · 2017: 12 · 2016: 11 · 2015: 9 · 2014: 5 · 2013: 4 · 2012: 6
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- farnesoid X receptor, liver immunity, autoimmune hepatitis, NKT cells, osteopontin, c-Jun, FXR agonists, liver injury, nuclear receptor signaling
- MeSH terms
- Receptor, Farnesoid X-Activated, Acute Disease, Animals, Bile Acids and Salts, Cell Line, Concanavalin A, Hepatitis, Interferon-gamma, Liver, Lymphocyte Activation, Mice, Inbred C57BL, Mitogens, Promoter Regions, Genetic, RNA, Messenger, Tumor Necrosis Factor-alpha, Interleukin-4, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Mice, Osteopontin, Natural Killer T-Cells
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