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Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs
Ece Yildiz1, Gaby El Alam2, Alessia Perino1
1Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Elife
|March 6, 2023
Summary
Fat overload reprograms biliary epithelial cells (BECs) into progenitor cells during early non-alcoholic fatty liver disease (NAFLD). This lipid-induced metabolic rewiring activates E2F transcription factors, driving cell cycle progression and regeneration.
Area of Science:
- Hepatology
- Cell Biology
- Metabolic Disease
Background:
- Biliary epithelial cells (BECs) activate into progenitors during liver injury, initiating ductular reaction (DR).
- Ductular reaction is a key feature of chronic liver diseases like non-alcoholic fatty liver disease (NAFLD).
- Early mechanisms of BEC activation in NAFLD remain poorly understood.
Purpose of the Study:
- To investigate the early events of BEC activation in the context of NAFLD.
- To elucidate the role of lipid accumulation in BEC reprogramming.
- To identify molecular pathways linking lipid metabolism to BEC progenitor cell activation.
Main Methods:
- Mice fed a high-fat diet to induce NAFLD.
- BEC-derived organoid models treated with fatty acids.
- Analysis of lipid accumulation, metabolic rewiring, and transcription factor activation (E2F).
Main Results:
- BECs accumulate lipids during high-fat diet feeding and fatty acid treatment.
- Lipid overload triggers metabolic rewiring, converting cholangiocytes into reactive BECs.
- Lipid overload activates E2F transcription factors, promoting cell cycle progression and glycolysis.
Conclusions:
- Fat overload is sufficient to reprogram BECs into progenitor cells in early NAFLD.
- Lipid metabolism critically influences BEC activation and the ductular reaction.
- This study reveals connections between lipid metabolism, stemness, and liver regeneration.
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