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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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Cites
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Identification of a nuclear receptor for bile acids
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Bile Acids: Natural Ligands for an Orphan Nuclear Receptor
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A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis
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Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c
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Eta-1 (Osteopontin): An Early Component of Type-1 (Cell-Mediated) Immunity
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Research works printed but not linked: 2
- 2005, Liver X receptor agonist inhibit cytokine-induced osteopontin expression in macrophages through interference with activator protein-1 signaling pathways., 59
- 2000, Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity., 860
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“Cipriani et al., 2011; Guo et al., 2015; Kawamata et al., 2003; Mencarelli et al., 2009; Sayin et al., 2013; Vavassori et al., 2009; Wang et al., 2011a ty bile l Enhances epithelial barrier function and maintenance by promoting epithelial production of IL-18 Levy et al., 2015 (Continued on next…”
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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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