Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs.

Autor:	Yildiz E; Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., El Alam G; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., Perino A; Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., Jalil A; Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., Denechaud PD; Center for Integrative Genomics, Université de Lausanne, Lausanne, Switzerland., Huber K; Center for Integrative Genomics, Université de Lausanne, Lausanne, Switzerland., Fajas L; Center for Integrative Genomics, Université de Lausanne, Lausanne, Switzerland.; INSERM, Occitanie, Montpellier, France., Auwerx J; Laboratory of Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., Sorrentino G; Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., Schoonjans K; Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2023 Mar 06; Vol. 12. Date of Electronic Publication: 2023 Mar 06.
DOI:	10.7554/eLife.81926
Abstrakt:	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 drive 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. Competing Interests: EY, GE, AP, AJ, PD, KH, LF, JA, GS, KS No competing interests declared (© 2023, Yildiz et al.)
Databáze:	MEDLINE
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