1. Stem Cells and Regenerative Medicine

Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs

  1. Ece Yildiz
  2. Gaby El Alam
  3. Alessia Perino
  4. Antoine Jalil
  5. Pierre-Damien Denechaud
  6. Katharina Huber
  7. Lluis Fajas
  8. Johan Auwerx
  9. Giovanni Sorrentino
  10. Kristina Schoonjans  Is a corresponding author
  1. École Polytechnique Fédérale de Lausanne, Switzerland
  2. Inserm UMR1048, France
  3. University of Lausanne, Switzerland
  4. University of Trieste, Italy
https://doi.org/10.7554/eLife.81926
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  1. Ece Yildiz
  2. Gaby El Alam
  3. Alessia Perino
  4. Antoine Jalil
  5. Pierre-Damien Denechaud
  6. Katharina Huber
  7. Lluis Fajas
  8. Johan Auwerx
  9. Giovanni Sorrentino
  10. Kristina Schoonjans
(2023)
Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs
eLife 12:e81926.
https://doi.org/10.7554/eLife.81926
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Abstract

During severe or chronic hepatic injury, biliary epithelial cells (BECs) undergo rapid activation into proliferating progenitors, a crucial step required to establish a regenerative process known as ductular reaction (DR). While DR is a hallmark of chronic liver diseases, including advanced stages of non-alcoholic fatty liver disease (NAFLD), the early events underlying BEC activation are largely unknown. Here, we demonstrate that BECs readily accumulate lipids during high-fat diet feeding in mice and upon fatty acid treatment in BEC-derived organoids. Lipid overload induces metabolic rewiring to support the conversion of adult cholangiocytes into reactive BECs. Mechanistically, we found that lipid overload activates the E2F transcription factors in BECs, which drives cell cycle progression while promoting glycolytic metabolism. These findings demonstrate that fat overload is sufficient to reprogram BECs into progenitor cells in the early stages of NAFLD and provide new insights into the mechanistic basis of this process, revealing unexpected connections between lipid metabolism, stemness, and regeneration.

Data availability

Computational analysis was performed using established packages mentioned in previous sections, and no new code was generated. RNA-Seq data have been deposited in GEO under accession code GSE217739. Two publicly available RNA-Seq datasets of mouse BECs with accession numbers GSE123133 (Aloia et al., 2019) and GSE125688 (Pepe-Mooney et al., 2019) were downloaded from the GEO and used for GSEA and over-representation enrichment analysis as mentioned previously. Source code is available at https://github.com/auwerxlab/Yildiz_eLife_2023.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ece Yildiz

    Laboratory of Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  2. Gaby El Alam

    Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  3. Alessia Perino

    Laboratory of Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  4. Antoine Jalil

    Laboratory of Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  5. Pierre-Damien Denechaud

    Institute of Metabolic and Cardiovascular Diseases, Inserm UMR1048, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3502-4814

  6. Katharina Huber

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  7. Lluis Fajas

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1283-9503

  8. Johan Auwerx

    Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  9. Giovanni Sorrentino

    Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
    Competing interests
    The authors declare that no competing interests exist.

  10. Kristina Schoonjans

    Laboratory of Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    For correspondence
    kristina.schoonjans@epfl.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1247-4265

Funding

École Polytechnique Fédérale de Lausanne

  • Kristina Schoonjans

Kristian Gerhard Jebsen Foundation

  • Kristina Schoonjans

Swiss National Science Foundation (310030_189178)

  • Kristina Schoonjans

Swiss National Science Foundation (31003A_179435)

  • Johan Auwerx

AIRC Start-Up 2020 (24322)

  • Giovanni Sorrentino

The authors declare no competing interests.

Ethics

Animal experimentation: All the animal experiments were authorized by the Veterinary Office of the Canton of Vaud, Switzerland, under license authorizations VD3721 and VD2627.b.

Copyright

© 2023, Yildiz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ece Yildiz
  2. Gaby El Alam
  3. Alessia Perino
  4. Antoine Jalil
  5. Pierre-Damien Denechaud
  6. Katharina Huber
  7. Lluis Fajas
  8. Johan Auwerx
  9. Giovanni Sorrentino
  10. Kristina Schoonjans
(2023)
Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs
eLife 12:e81926.
https://doi.org/10.7554/eLife.81926

Share this article

https://doi.org/10.7554/eLife.81926

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