Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs
- École Polytechnique Fédérale de Lausanne, Switzerland
- Inserm UMR1048, France
- University of Lausanne, Switzerland
- University of Trieste, Italy
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.
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Hepatic lipid overload triggers biliary epithelial cell activation via E2FsNCBI Gene Expression Omnibus, GSE217739.
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Transcriptonal and epigenetic changes of adult liver cells in vivo and in vitroNCBI Gene Expression Omnibus, GSE123133.
Article and author information
Author details
Pierre-Damien Denechaud
Kristina Schoonjans
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.
Reviewing Editor
- Peter Tontonoz, University of California, Los Angeles, United States
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.
Version history
- Received: July 16, 2022
- Preprint posted: July 28, 2022 (view preprint)
- Accepted: March 3, 2023
- Accepted Manuscript published: March 6, 2023 (version 1)
- Version of Record published: March 21, 2023 (version 2)
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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Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs
eLife 12:e81926.
https://doi.org/10.7554/eLife.81926
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