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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.<\/jats:p>","DOI":"10.7554\/elife.81926","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T04:10:39Z","timestamp":1665979839000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.81926","source":"Crossref","is-referenced-by-count":8,"title":["Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs"],"prefix":"10.7554","volume":"12","author":[{"given":"Ece","family":"Yildiz","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02s376052","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaby","family":"El Alam","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02s376052","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5434-3266","authenticated-orcid":true,"given":"Alessia","family":"Perino","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02s376052","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Jalil","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02s376052","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3502-4814","authenticated-orcid":true,"given":"Pierre-Damien","family":"Denechaud","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Integrative Genomics, Universit\u00e9 de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Huber","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Integrative Genomics, Universit\u00e9 de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-9503","authenticated-orcid":true,"given":"Lluis","family":"Fajas","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Integrative Genomics, Universit\u00e9 de Lausanne","place":["Lausanne, Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/03fkrcm40","id-type":"ROR","asserted-by":"publisher"}],"name":"INSERM, Occitanie","place":["Montpellier, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Auwerx","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02s376052","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Sorrentino","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02s376052","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1247-4265","authenticated-orcid":true,"given":"Kristina","family":"Schoonjans","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02s376052","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2023,3,6]]},"reference":[{"key":"bib1","article-title":"Yildiz_eLife_2023","volume-title":"Software Heritage","author":"Alam","year":"2023","unstructured":"Alam GE. 2023. 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