Cited by 65Liver Diseases and ImmunityDrug Transport and Resistance MechanismsImmunotoxicology and immune responses

24-Norursodeoxycholic acid reshapes immunometabolism in CD8(+) T cells and alleviates hepatic inflammation

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Zhu, Ci, Boucheron, Nicole, Müller, André C., Májek, Peter, Claudel, Thierry, Halilbasic, Emina, Baazim, Hatoon, Lercher, Alexander +21 more·2021·Journal of Hepatology

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Abstract

Abstract Background & Aims 24-NorUrsodeoxycholic acid (NorUDCA) is novel therapy for immune-mediated liver diseases such as primary sclerosing cholangitis (PSC) where dysregulated T cells including CD8 + T cells cause liver immunopathology. We hypothesized that NorUDCA may directly modulate CD8 + T cell effector function thus contributing to its therapeutic efficacy independent of anti-cholestatic effects. Methods NorUDCA effects on CD8 + T cell function in vivo were investigated in a hepatic injury model system induced by excessive CD8 + T cell immune response upon non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Mechanistic studies included molecular and biochemical approaches, flow cytometry and metabolic assays in mouse CD8 + T cells in vitro . Mass spectrometry (MS) was used to identify potential targets modulated by NorUDCA in CD8 + T cells. NorUDCA signaling effects observed in murine systems were validated in peripheral T cells from healthy volunteers and PSC patients. Results In vivo NorUDCA ameliorated hepatic injury and systemic inflammation upon LCMV infection. Mechanistically, NorUDCA demonstrated a strong immunomodulatory efficacy in CD8 + T cells affecting lymphoblastogenesis, mTORC1 signaling and glycolysis of CD8 + T cells. With MS, we identified that NorUDCA regulates CD8 + T cells via targeting mTORC1. NorUDCA’s impact on mTORC1 signaling was further confirmed in circulating human CD8 + T cells. Conclusions NorUDCA possesses a yet-unrecognized direct modulatory potency on CD8 + T cells and attenuates excessive CD8 + T cell hepatic immunopathology. These findings may be relevant for treatment of immune-mediated liver diseases such as PSC and beyond.

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Crossref · 10.1016/j.jhep.2021.06.036

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  • Norucholic acid has shown anticholestatic, anti-inflammatory and anti-fibrotic properties in preclinical models and is being tested for MASH with initial results showing improvement in ALT and liver steatosis.

    “A synthetic UDCA derivative, 24norursodeoxycholic acid (norucholic acid), has shown anticholestatic, anti-in fl ammatory and anti- fi brotic properties in preclinical models 376 and is being tested for MASH with initial results showing improvement in ALT and liver steatosis.”

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Authors
Zhu, C., Boucheron, N., Müller, A. C., Májek, P., Claudel, T., Halilbasic, E., Baazim, H., Lercher, A., Viczenczova, C., Hainberger, D., Preglej, T., Sandner, L., Alteneder, M., Gülich, A. F., Khan, M., Hamminger, P., Remetic, J., Ohradanova-Repic, A., Schatzlmaier, P., Donner, C., Fuchs, C. D., Stojakovic, T., Scharnagl, H., Sakaguchi, S., Weichhart, T., Bergthaler, A., Stockinger, H., Ellmeier, W., & Trauner, M.
Affiliations
  • Medical University of Vienna (AT)
  • Austrian Academy of Sciences (AT)
  • Medical University of Graz (AT)
Corresponding author
  • Boucheron, Nicole
  • Trauner, Michael
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2021-11
Volume
75
Issue
5
Pages
1164-1176
ISSN
0168-8278 (ISSN-L)
OpenAlex
W3180833467
Cited by
65
References
34
Citations by year
2026: 13 · 2025: 16 · 2024: 18 · 2023: 11 · 2022: 6 · 2021: 1
FWCI
5.00
Type
journal article
Language
en
Open access
Locations
  • Journal of Hepatology (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Austrian Science Fund (DK-IAI W1212, F3517, F7004, F7005, F7310, I2755, P24265, P26193, P27747, P29790, P30885)
  • Horizon 2020 (677006)
  • Horizon 2020 Framework Programme (683356-FOLSMART)
  • European Research Council
  • Österreichischen Akademie der Wissenschaften
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords
primary sclerosing cholangitis, CD8+ T cells, immunometabolism, mTORC1 signaling, liver inflammation, cholestasis, lymphocytic choriomeningitis virus, bile acids, immune-mediated liver disease, T cell differentiation
MeSH terms
Animals, Disease Models, Animal, Inflammation, Liver, Mice, Inbred C57BL, Ursodeoxycholic Acid, CD8-Positive T-Lymphocytes, Mice

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