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These systemic and intracellular pathways are interdependent, but it is unclear whether and how they integrate into a single cellular circuit. Here, we report that mouse liver wrappER, a distinct endoplasmic reticulum (ER) compartment with apparent fatty acid- and VLDL-secretion functions, connects peroxisomes and mitochondria. Correlative light electron microscopy, quantitative serial section electron tomography and three-dimensional organelle reconstruction analysis show that the number of peroxisome-wrappER-mitochondria complexes changes throughout fasting-to-feeding transitions and doubles when VLDL synthesis stops following acute genetic ablation of Mttp in the liver. Quantitative proteomic analysis of peroxisome-wrappER-mitochondria complex-enriched fractions indicates that the loss of Mttp upregulates global fatty acid \u03b2-oxidation, thereby integrating the dynamics of this three-organelle association into hepatic fatty acid flux responses. Therefore, liver lipid homeostasis occurs through the convergence of systemic and intracellular fatty acid-elimination pathways in the peroxisome-wrappER-mitochondria complex.<\/jats:p>","DOI":"10.1242\/jcs.259091","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T05:10:16Z","timestamp":1634793016000},"source":"Crossref","is-referenced-by-count":47,"title":["A three-organelle complex made by wrappER contacts with peroxisomes and mitochondria responds to liver lipid flux changes"],"prefix":"10.1242","volume":"135","author":[{"given":"Nicol\u00f2","family":"Ilacqua","sequence":"first","affiliation":[{"name":"Laval University 1 Graduate Program in Neuroscience, Faculty of Medicine , , Quebec, QC, G1V 0A6 , Canada"},{"name":"Brain Research Center 2 Mitochondria Biology Laboratory , , Quebec, QC, G1E 1T2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Anastasia","sequence":"additional","affiliation":[{"name":"Laval University 1 Graduate Program in Neuroscience, Faculty of Medicine , , Quebec, QC, G1V 0A6 , Canada"},{"name":"Brain Research Center 2 Mitochondria Biology Laboratory , , Quebec, QC, G1E 1T2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Raimondi","sequence":"additional","affiliation":[{"name":"Experimental Imaging Center, San Raffaele Scientific Institute 3 , Milan, 20132 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3663-9677","authenticated-orcid":false,"given":"Philippe","family":"Lemieux","sequence":"additional","affiliation":[{"name":"Brain Research Center 2 Mitochondria Biology Laboratory , , Quebec, QC, G1E 1T2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas Q.","family":"de Aguiar Vallim","sequence":"additional","affiliation":[{"name":"Geffen School of Medicine, University of California, Los Angeles 4 Department of Biological Chemistry , , Los Angeles, CA 90095 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin","family":"Toth","sequence":"additional","affiliation":[{"name":"University of Ottawa 5 Department of Cellular and Molecular Medicine , , Ottawa, ON, K1H 8M5 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene V.","family":"Koonin","sequence":"additional","affiliation":[{"name":"National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health 6 , Bethesda, MD 20894 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4235-7708","authenticated-orcid":false,"given":"Luca","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Brain Research Center 2 Mitochondria Biology Laboratory , , Quebec, QC, G1E 1T2 , Canada"},{"name":"Laval University 7 Deptartment of Molecular Biology, Medical Biochemistry, and Pathology, Faculty of Medicine , , Quebec, QC, G1V 0A6 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2021,11,2]]},"reference":[{"key":"2024061307334284700_JCS259091C1","doi-asserted-by":"publisher","first-page":"108873","DOI":"10.1016\/j.celrep.2021.108873","article-title":"Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis","volume":"34","author":"Anastasia","year":"2021","journal-title":"Cell Rep."},{"key":"2024061307334284700_JCS259091C2","doi-asserted-by":"publisher","first-page":"ENEURO.0259-19.2019","DOI":"10.1523\/ENEURO.0259-19.2019","article-title":"Changing the way we report, interpret, and discuss our results to rebuild trust in our research","volume":"6","author":"Bernard","year":"2019","journal-title":"eNeuro"},{"key":"2024061307334284700_JCS259091C3","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","article-title":"ClueGO: A Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks","volume":"25","author":"Bindea","year":"2009","journal-title":"Bioinformatics"},{"key":"2024061307334284700_JCS259091C4","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1146\/annurev-biochem-062917-011852","article-title":"Retrospective on cholesterol homeostasis: the central role of scap","volume":"87","author":"Brown","year":"2018","journal-title":"Annu. 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