{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:17:40Z","timestamp":1792034260895,"version":"4.4.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:00:00Z","timestamp":1665446400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/ http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims:<\/jats:title>\n            <jats:p>Receptor\u2010interacting protein kinase 3 (RIPK3) mediates NAFLD progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>Functional studies evaluating mitochondria and LD biology were performed in wild\u2010type (WT) and <jats:italic toggle=\"yes\">Ripk3<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice fed a choline\u2010deficient, amino acid\u2010defined (CDAA) diet for 32 and 66\u2009weeks and in CRISPR\u2010Cas9 <jats:italic toggle=\"yes\">Ripk3<\/jats:italic>\u2010null fat\u2010loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3, and disease severity was also addressed in a cohort of patients with NAFLD and in <jats:italic toggle=\"yes\">PLIN1<\/jats:italic>\u2010associated familial partial lipodystrophy. <jats:italic toggle=\"yes\">Ripk3<\/jats:italic> deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet\u2013fed mice and fat\u2010loaded hepatocytes. <jats:italic toggle=\"yes\">Ripk3<\/jats:italic> deficiency was accompanied by a strong upregulation of antioxidant systems, leading to diminished oxidative stress upon fat loading both in vivo and in vitro. Strikingly, <jats:italic toggle=\"yes\">Ripk3<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. <jats:italic toggle=\"yes\">Ripk3<\/jats:italic> deficiency upregulated adipocyte and hepatic levels of LD\u2010associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in <jats:italic toggle=\"yes\">Ripk3<\/jats:italic>\n                                 <jats:sup>\n                                    \u2212\/\u2212\n                                 <\/jats:sup> hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic <jats:italic toggle=\"yes\">PLIN1<\/jats:italic> frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n                                 <jats:italic toggle=\"yes\">Ripk3<\/jats:italic> deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32756","type":"journal-article","created":{"date-parts":[[2022,8,27]],"date-time":"2022-08-27T06:06:56Z","timestamp":1661580416000},"page":"1319-1334","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":54,"title":["RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease"],"prefix":"10.1097","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3011-4941","authenticated-orcid":false,"given":"Marta B.","family":"Afonso","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tawhidul","family":"Islam","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of 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University of Coimbra, Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Teixeira","sequence":"additional","affiliation":[{"name":"CNC \u2010 Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana C.","family":"Silva","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Wendum","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm, Centre de Recherche Saint\u2010Antoine, Paris, France"},{"name":"Service d'Anatomo\u2010Pathologie, Service d'H\u00e9patologie, Centre de R\u00e9f\u00e9rence Maladie Rare Maladies Inflammatoires des Voies Biliaires\u2010H\u00e9patites Auto\u2010immunes, Paris, 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui E.","family":"Castro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5201-9948","authenticated-orcid":false,"given":"Paulo J.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"CNC \u2010 Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Prip\u2010Buus","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Institut Cochin, INSERM, CNRS, Paris, 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