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 be mediated not only by Kupffer cells but also by hepatocytes and NKT cells.
“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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Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 234 · see citing works
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“anti-inflammatory response with, in particular, a remarkable decrease in the number of NKCs, both locally in the MLNs and systemically in the spleen, consistent with findings by others on the hepatic level.(50) As a logical consequence, IFN-g levels (in parallel with the decreased number of NKCs in the INT-747etreated…”
ResultPoupon, R. Y. (2012) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/s2210-7401(12)70015-3 · Cited by 224 · see citing works
Recent advances in the development of farnesoid X receptor agonists.
Ali, A. H., Carey, E. J., & Lindor, K. D. (2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2305-5839.2014.12.06 · Cited by 222 · see citing works
“OCA treatment reduced AST and plasma levels of interferon-ɣ and tumor necrosis factor-α in a mouse model of autoimmune hepatitis (108), reduced the expression of profibrotic and fibrosis markers in a mouse model of nephropathy (109), and attenuated colon injury by increasing colon expression of FXR and SHP and reducin…”
BackgroundCauses and mechanisms of adipocyte enlargement and adipose expansion
Haczeyni, F., Bell-Anderson, K. S., & Farrell, G. C. (2017) · Obesity Reviews · doi:10.1111/obr.12646 · Cited by 221 · see citing works
“receptor (FXR) and influences liver immunity in both humans (139) and mice (140).”
BackgroundThe cross talk between microbiota and the immune system: metabolites take center stage
Shapiro, H., Thaiss, C. A., Levy, M., & Elinav, E. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.07.003 · Cited by 189 · see citing works
“In addition, FXR signaling may control expression of osteopontin in liver NKT cells in hepatitis [45].”
BackgroundGut microbiota derived bile acid metabolites maintain the homeostasis of gut and systemic immunity
Su, L., Gao, Y., & Yang, R. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1127743 · Cited by 167 · see citing works
“In addition, FXR also activates SHP to inhibit NFkB, AP-1 and NLRP3 (56–59), and is recruited to the iNOS and IL1b promoters to stabilize the NCoR1 complexes, which can make these genes in the basal state (60).”
BackgroundBile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease
Gadaleta, R. M., van Mil, S. W. C., Oldenburg, B., Siersema, P. D., Klomp, L. W. J., & van Erpecum, K. J. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.04.006 · Cited by 147 · see citing works
Cross talk between neutrophils and the microbiota
Zhang, D., & Frenette, P. S. (2019) · Blood · doi:10.1182/blood-2018-11-844555 · Cited by 148 · see citing works
The role of bile acids in cholestatic liver injury
Cai, S.-Y., & Boyer, J. (2020) · Annals of Translational Medicine · doi:10.21037/atm-20-5110 · Cited by 110 · see citing works
“FXR is also expressed in liver NKT cells and when activated in-vivo inhibits their ability to produce osteopontin, a potent pro-inflammatory mediator, in an acute liver injury model induced by concanavalin A (37).”
BackgroundBile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease
Jiao, T., Ma, Y., Guo, X., Ye, Y., & Xie, C. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-022-00880-z · Cited by 122 · see citing works
“Induction of SHP by activation of FXR prevents the transcription activity of osteopontin induced by c-Jun and reduces osteopontin production, an extracellular matrix protein and immunoregulatory cytokine derived from NKT cells [103].”
BackgroundBile acids as inflammatory mediators and modulators of intestinal permeability
Calzadilla, N., Comiskey, S., Dudeja, P. K., Saksena, S., Gill, R. K., & Alrefai, W. A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1021924 · Cited by 119 · see citing works
“Furthermore, FXR activation in NKT cells has been shown to inhibit the production of osteopontin, a pro-inflammatory cytokine, through SHP (40).”
BackgroundInfluentialMencarelli, A., Cipriani, S., Renga, B., Bruno, A. M., D’Amore, C., Distrutti, E., & Fiorucci, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045425 · Cited by 115 · see citing works
“Results from the present study suggest that the shift toward a more tolerogenic immune-phenotype caused by VSL#3 intervention, could be mediated by the regulation of the expression/ activity of members of nuclear receptor superfamily [55–59].”
BackgroundBile acids as key modulators of the brain-Gut-Microbiota axis in alzheimer’s disease
Mulak, A. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210608 · Cited by 114 · see citing works
“In fact, FXR and TGR5 knockout mice develop spontaneous intestinal inflammation [103, 104].”
BackgroundLiu, N., Meng, Z., Lou, G., Zhou, W., Wang, X., Zhang, Y., Zhang, L., Liu, X., Yen, Y., Lai, L. L., et al. (2012) · Molecular Endocrinology · doi:10.1210/me.2011-1383 · Cited by 109 · see citing works
Interactions between bile salts, gut microbiota, and hepatic innate immunity
Schubert, K. A., Damink, S. W. M. O., von Bergen�, M., & Schaap, F. G. (2017) · Immunological Reviews · doi:10.1111/imr.12579 · Cited by 102 · see citing works
Cariello, M., Piccinin, E., & Moschetta, A. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.01.012 · Cited by 103 · see citing works
Bile acids activated receptors in inflammatory bowel disease
Biagioli, M., Marchianò, S., Carino, A., Di Giorgio, C., Santucci, L., Distrutti, E., & Fiorucci, S. (2021) · Cells · doi:10.3390/cells10061281 · Cited by 103 · see citing works
“On the contrary, in the presence of an agonist, such as obeticholic acid (OCA, also known as INT-747), FXR is recruited to the iNOS and IL-1β promoters and stabilizes the NCoR1 complexes on the promoters of these two genes, causing a trans-repression [42] (Figure 2A).”
BackgroundSelf-citationClaudel, T., Zollner, G., Wagner, M., & Trauner, M. A. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.12.021 · Cited by 101 · see citing works
Cariello, M., Piccinin, E., García‐Irigoyen, O., Sabbà, C., & Moschetta, A. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.09.019 · Cited by 97 · see citing works
Versatile Triad Alliance: Bile Acid, Taurine and Microbiota
Duszka, K. (2022) · Cells · doi:10.3390/cells11152337 · Cited by 100 · see citing works
D’Amore, C., Leva, F. S. D., Sepe, V., Renga, B., Gaudio, C. D., D’Auria, M. V., Zampella, A., Fiorucci, S., & Limongelli, V. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401873d · Cited by 97 · see citing works
Huang, X., Zhao, W., & Huang, W. (2014) · Acta Pharmacologica Sinica · doi:10.1038/aps.2014.117 · Cited by 95 · see citing works
Thibaut, R., Gage, M., Pineda‐Torra, I., Chabrier, G., Venteclef, N., & Alzaïd, F. (2021) · FEBS Journal · doi:10.1111/febs.15877 · Cited by 95 · see citing works
Trivedi, P. J., Hirschfield, G. M., Adams, D., & Vierling, J. M. (2024) · Gastroenterology · doi:10.1053/j.gastro.2024.01.049 · Cited by 98 · see citing works
Nuclear receptors as drug targets in cholestasis and drug-induced hepatotoxicity
Zollner, G., Wagner, M., & Trauner, M. A. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.03.005 · Cited by 89 · see citing works
“…C virus replication making it a very attractive target for various hepatobiliary and gastrointestinal disorders (Huang et al., 2006; Inagaki et al., 2006; Modica & Moschetta, 2006; Kim et al., 2007b; Yang et al., 2007; Scholtes et al., 2008; Mencarelli et al., 2009; Vavassori et al., 2009).”
BackgroundHo, P. P.-K., & Steinman, L. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1524890113 · Cited by 83 · see citing works
“The bile acid–FXR interaction plays an integral role in regulating hepatic inflammation and regeneration, and FXR activation has been shown to attenuate liver injury in a rodent model of autoimmune hepatitis (7).”
BackgroundImmunology of bile acids regulated receptors
Fiorucci, S., Marchianò, S., Urbani, G., Giorgio, C. D., Distrutti, E., Zampella, A., & Biagioli, M. (2024) · Progress in Lipid Research · doi:10.1016/j.plipres.2024.101291 · Cited by 84 · see citing works
Obeticholic Acid: An Update of Its Pharmacological Activities in Liver Disorders
Fiorucci, S., Giorgio, C. D., & Distrutti, E. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_227 · Cited by 82 · see citing works
The Immunomodulatory Role of Bile Acids
Sipka, S., & Bruckner, G. G. (2014) · International Archives of Allergy and Immunology · doi:10.1159/000366100 · Cited by 80 · see citing works
Schumacher, J. D., Kong, B., Wu, B. J., Rizzolo, D., Armstrong, L. E., Chow, M. D., Goedken, M. J., Lee, Y., & Guo, G. L. (2019) · Hepatology · doi:10.1002/hep.30810 · Cited by 80 · see citing works
“It has been previously reported that FXR activation mitigates hepatic inflammation.(25-29) In agreement, in this study, TBAP size and expression of an FXR target gene, Shp, were correlated to Tnfα and Icam1 expression.”
BackgroundCapsaicin shapes gut microbiota and pre-metastatic niche to facilitate cancer metastasis to liver
Cheng, P., Wu, J., Zong, G., Wang, F., Deng, R., Tao, R., Qian, C., Shan, Y., Wang, A., Zhao, Y., et al. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2022.106643 · Cited by 75 · see citing works
Immunomodulatory functions of FXR
Fiorucci, S., Zampella, A., Ricci, P., Distrutti, E., & Biagioli, M. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2022.111650 · Cited by 73 · see citing works
Bile acid-activated receptors and the regulation of macrophages function in metabolic disorders
Fiorucci, S., Baldoni, M., Ricci, P., Zampella, A., Distrutti, E., & Biagioli, M. (2020) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2020.04.008 · Cited by 69 · see citing works
Biagioli, M., Carino, A., Fiorucci, C., Marchianò, S., Giorgio, C. D., Roselli, R., Magro, M., Distrutti, E., Bereshchenko, O., Scarpelli, P., et al. (2019) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2019.06.003 · Cited by 67 · see citing works
Calmus, Y., & Poupon, R. (2014) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/j.clinre.2014.07.007 · Cited by 69 · see citing works
Obeticholic acid for the treatment of primary biliary cirrhosis
Trivedi, P. J., Hirschfield, G. M., & Gershwin, M. E. (2015) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2015.1092381 · Cited by 65 · see citing works
Schumacher, J. D., & Guo, G. L. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_228 · Cited by 64 · see citing works
Burrin, D. G., Stoll, B., & Moore, D. D. (2013) · Journal of Animal Science · doi:10.2527/jas.2013-6331 · Cited by 60 · see citing works
“…targets FXR, called obeticholic acid (6-ethyl chenodeoxycholic acid; INT-747), that has been shown to protect against cholestatic liver injury and fi brosis, experimental colitis, and augment innate immunity in mice (Fiorucci et al., 2004, 2005; Mencarelli et al., 2009; Cipriani et al., 2011).”
BackgroundGut Microbial Metabolites on Host Immune Responses in Health and Disease
Yoon, J.-H., Do, J.-S., Velankanni, P., Lee, C., & Kwon, H. (2023) · Immune Network · doi:10.4110/in.2023.23.e6 · Cited by 61 · see citing works
“(81) demonstrated that FXR acts directly on NKT cells in the liver and reduces production of osteopontin, an immunoregulatory cytokine, resulting in the attenuation of liver injury by hepatitis.”
BackgroundWu, H., Liu, G., He, Y., Da, J., & Xie, B.-Q. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.05.022 · Cited by 57 · see citing works
NOX as a Therapeutic Target in Liver Disease
Matuz‐Mares, D., Vázquez‐Meza, H., & Vilchis‐Landeros, M. M. (2022) · Antioxidants · doi:10.3390/antiox11102038 · Cited by 55 · see citing works
“Additionally, by being a ligand for the G-protein coupled receptor TGR5 [101] and activating mitogen-activated protein kinase pathways [102], they contribute to several additional cell signaling and immunoregulatory processes [103,104].”
BackgroundMetabolic regulation in the immune response to cancer
Wu, Q., Yu, X., Li, J., Sun, S., & Tu, Y. (2021) · 癌症：英文版 · doi:10.1002/cac2.12182 · Cited by 56 · see citing works
“In addition to macrophages, hepatocytes and natural killer T (NKT) cells are also involved in the BAR deficiency-mediated activation of inflammation [229].”
BackgroundThe pathophysiological function of non-gastrointestinal farnesoid X receptor
Yan, N., Yan, T., Xia, Y., Hao, H., Wang, G., & Gonzalez, F. J. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107867 · Cited by 54 · see citing works
Regulation of gut microbiota-bile acids axis by probiotics in inflammatory bowel disease
Li, L., Liu, T., Gu, Y., Wang, X., Xie, R., Sun, Y., Wang, B., & Cao, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.974305 · Cited by 51 · see citing works
“TGR5 activation shifts intestinalmacrophages that are treated with LPS from M1 to M2; decreases the expression of TNF-a, IL-1b, IFN-g, IL-6, and IL-12; and elevates the level of IL-10.”
BackgroundInfluentialSignaling from Intestine to the Host: How Bile Acids Regulate Intestinal and Liver Immunity
Biagioli, M., & Carino, A. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_225 · Cited by 50 · see citing works
Farnesoid-X receptor as a therapeutic target for inflammatory bowel disease and colorectal cancer
Zhou, M.-J., Wang, D., Li, X., Cao, Y., Yi, C.-X., Ocansey, D. K. W., Zhou, Y., & Mao, F. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1016836 · Cited by 51 · see citing works
“, 2022), the FXR/SHP signaling axis is effectively activated and the development of inflammation is inhibited (Mencarelli et al., 2009).”
BackgroundFarnesoid X Receptor Agonists: A Promising Therapeutic Strategy for Gastrointestinal Diseases
Almeqdadi, M., & Gordon, F. D. (2023) · Gastro Hep Advances · doi:10.1016/j.gastha.2023.09.013 · Cited by 47 · see citing works
“12,13 Therefore, FXR agonists may have potential therapeutic applications in the treatment of in fl ammatory bowel disease (IBD) and other autoimmune disorders, where dysregulated innate immune responses play a crucial role in the pathogenesis of the disease.”
BackgroundHaczeyni, F., Poekes, L., Wang, H., Mridha, A. R., Barn, V., Haigh, W. G., Ioannou, G. N., Yeh, M. M., Leclercq, I. A., Teoh, N., et al. (2016) · Obesity · doi:10.1002/oby.21701 · Cited by 46 · see citing works
“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 47 · see citing works
“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 44 · see citing works
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 · see citing works
“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 · see citing works
Traussnigg, S., Halilbasic, E., Hofer, H., Munda, P., Stojaković, T., Fauler, G., Kashofer, K., Krššák, M., Wolzt, M., & Trauner, M. A. (2020) · Wiener klinische Wochenschrift · doi:10.1007/s00508-020-01735-5 · Cited by 42 · see citing works
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 · see citing works
“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 · see citing works
“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 42 · see citing works
Halilbasic, E., Fuchs, C. D., Traussnigg, S., & Trauner, M. A. (2016) · Digestive Diseases · doi:10.1159/000445268 · Cited by 39 · see citing works
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 · see citing works
“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 38 · see citing works
“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 41 · see citing works
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 · see citing works
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 · see citing works
“(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 35 · see citing works
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 · see citing works
“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 · see citing works
“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 32 · see citing works
Liu, R., Wang, J., Liu, Y., Gao, Y., & Yang, R. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217115 · Cited by 32 · see citing works
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 32 · see citing works
“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 31 · see citing works
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 30 · see citing works
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 · see citing works
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 · see citing works
“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 30 · see citing works
“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 29 · see citing works
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 · see citing works
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 28 · see citing works
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 28 · see citing works
“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 28 · see citing works
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 · see citing works
Urbani, G., Rondini, E., Distrutti, E., Marchianò, S., Biagioli, M., & Fiorucci, S. (2025) · Cells · doi:10.3390/cells14080595 · Cited by 24 · see citing works
- 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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