Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs

Abstract
Data availability
Article and author information
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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

1. Schoonjans K
2. et al
(2023) Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs
NCBI Gene Expression Omnibus, GSE217739.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE217739

The following previously published data sets were used

1. Aloia L
2. Vernaz G
3. Huch M
(2019) Transcriptonal and epigenetic changes of adult liver cells in vivo and in vitro
NCBI Gene Expression Omnibus, GSE123133.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE123133
1. Pepe-Mooney BJ
2. Dill MT
3. Alemany A
4. Ordovas-Montanes J
5. Matsushita Y
6. Rao A
7. Sen A
8. Miyazaki M
9. Anakk S
10. Dawson P
11. Ono N
12. Shalek AK
13. van Oudenaarden A
14. Camargo FD
(2019) Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration
NCBI Gene Expression Omnibus, GSE125688.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE125688

Article and author information

Author details

Ece Yildiz

Laboratory of Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
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.
Alessia Perino

Laboratory of Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
Antoine Jalil

Laboratory of Metabolic Signaling, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
Pierre-Damien Denechaud

Institute of Metabolic and Cardiovascular Diseases, Inserm UMR1048, Toulouse, France

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3502-4814
Katharina Huber

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
Lluis Fajas

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1283-9503
Johan Auwerx

Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
Giovanni Sorrentino

Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy

Competing interests
The authors declare that no competing interests exist.
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.

"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

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.