RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease
dc.contributor.author | Afonso, Marta Bento | |
dc.contributor.author | Rodrigues, Pedro M. | |
dc.contributor.author | Mateus Pinheiro, Miguel | |
dc.contributor.author | Simao, André L. | |
dc.contributor.author | Gaspar, María M. | |
dc.contributor.author | Majdi, Amine | |
dc.contributor.author | Arretxe Oliden, Enara | |
dc.contributor.author | Alonso, Cristina | |
dc.contributor.author | Santos Laso, Álvaro | |
dc.contributor.author | Jiménez Agüero, Raúl | |
dc.contributor.author | Eizaguirre Letamendia, Emma | |
dc.contributor.author | Bujanda Fernández de Pierola, Luis | |
dc.contributor.author | Pareja Megía, María J. | |
dc.contributor.author | Bañales Asurmendi, Jesús María | |
dc.contributor.author | ratziu, Vlad | |
dc.contributor.author | Gautheron, Jeremie | |
dc.contributor.author | Castro, Rui E. | |
dc.contributor.author | Rodrigues, Cecilia M. P. | |
dc.date.accessioned | 2021-12-20T09:44:01Z | |
dc.date.available | 2021-12-20T09:44:01Z | |
dc.date.issued | 2021-12 | |
dc.identifier.citation | GUT 70(12) : 2359-2372 (2021) | es_ES |
dc.identifier.issn | 0017-5749 | |
dc.identifier.issn | 1468-3288 | |
dc.identifier.uri | http://hdl.handle.net/10810/54552 | |
dc.description.abstract | [EN]Objective Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD. Design RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3(-/-)) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks. Results RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3(-/-) mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3(-/-) mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor. (PPAR.) was increased in Ripk3(-/-) mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPAR. in controlling fat deposition and fibrosis. Conclusion Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression. | es_ES |
dc.description.sponsorship | Main funding is provided by FEDER funds through the COMPETE programme and by national funds through Fundacao para a Ciencia e a Tecnologia to CMPR (grants SAICTPAC/0019/2015-LISBOA-01-0145--FEDER-016405 and PTDC/MED-FAR/29097/2017 -LISBOA-01-0145-FEDER-029097). Additional funding comes from research grant APEF (Portuguese Association for the Study of Liver)/BAYER 2020 to MBA. JG is funded by the Fondation pour la Recherche Medicale (ARF20170938613), the Institute of Cardiometabolism and Nutrition (PAP17NECJG), the Societe Francophone du Diabete (R19114DD) and the Mairie de Paris (Emergences -R18139DD). MBA, PMR, MMP and ALS were investigators or students funded by Fundacao para a Ciencia e a Tecnologia. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | BMJ | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/3.0/es/ | * |
dc.subject | activated receptor-gamma | es_ES |
dc.subject | hepatocellular-carcinoma | es_ES |
dc.subject | choline-deficient | es_ES |
dc.subject | gene-expression | es_ES |
dc.subject | fibrosis | es_ES |
dc.subject | cell | es_ES |
dc.subject | mice | es_ES |
dc.subject | hepatocarcinogenesis | es_ES |
dc.subject | necroptosis | es_ES |
dc.subject | protects | es_ES |
dc.title | RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © Author(s) (or their employer(s)) 2021. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. | es_ES |
dc.rights.holder | Atribución-NoComercial 3.0 España | * |
dc.relation.publisherversion | https://gut.bmj.com/content/70/12/2359 | es_ES |
dc.identifier.doi | 10.1136/gutjnl-2020-321767 | |
dc.departamentoes | Medicina | es_ES |
dc.departamentoeu | Medikuntza | es_ES |
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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.