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RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease
Receptor‐interacting 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. APPROACH AND RESULTS: Functional studies evalua...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10026966/ https://www.ncbi.nlm.nih.gov/pubmed/36029129 http://dx.doi.org/10.1002/hep.32756 |
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author | Afonso, Marta B. Islam, Tawhidul Magusto, Julie Amorim, Ricardo Lenoir, Véronique Simões, Rui F. Teixeira, José Silva, Liana C. Wendum, Dominique Jéru, Isabelle Vigouroux, Corinne Castro, Rui E. Oliveira, Paulo J. Prip‐Buus, Carina Ratziu, Vlad Gautheron, Jérémie Rodrigues, Cecília M. P. |
author_facet | Afonso, Marta B. Islam, Tawhidul Magusto, Julie Amorim, Ricardo Lenoir, Véronique Simões, Rui F. Teixeira, José Silva, Liana C. Wendum, Dominique Jéru, Isabelle Vigouroux, Corinne Castro, Rui E. Oliveira, Paulo J. Prip‐Buus, Carina Ratziu, Vlad Gautheron, Jérémie Rodrigues, Cecília M. P. |
author_sort | Afonso, Marta B. |
collection | PubMed |
description | Receptor‐interacting 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. APPROACH AND RESULTS: Functional studies evaluating mitochondria and LD biology were performed in wild‐type (WT) and Ripk3 (−/−) mice fed a choline‐deficient, amino acid‐defined (CDAA) diet for 32 and 66 weeks and in CRISPR‐Cas9 Ripk3‐null fat‐loaded 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 PLIN1‐associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet–fed mice and fat‐loaded hepatocytes. Ripk3 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, Ripk3 (−/−) hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD‐associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3 ( −/− ) hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy. CONCLUSIONS: Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD. |
format | Online Article Text |
id | pubmed-10026966 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-100269662023-03-21 RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease Afonso, Marta B. Islam, Tawhidul Magusto, Julie Amorim, Ricardo Lenoir, Véronique Simões, Rui F. Teixeira, José Silva, Liana C. Wendum, Dominique Jéru, Isabelle Vigouroux, Corinne Castro, Rui E. Oliveira, Paulo J. Prip‐Buus, Carina Ratziu, Vlad Gautheron, Jérémie Rodrigues, Cecília M. P. Hepatology Original Articles: Steatohepatitis Receptor‐interacting 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. APPROACH AND RESULTS: Functional studies evaluating mitochondria and LD biology were performed in wild‐type (WT) and Ripk3 (−/−) mice fed a choline‐deficient, amino acid‐defined (CDAA) diet for 32 and 66 weeks and in CRISPR‐Cas9 Ripk3‐null fat‐loaded 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 PLIN1‐associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet–fed mice and fat‐loaded hepatocytes. Ripk3 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, Ripk3 (−/−) hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD‐associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3 ( −/− ) hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy. CONCLUSIONS: Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD. Lippincott Williams & Wilkins 2023-04 2022-10-11 /pmc/articles/PMC10026966/ /pubmed/36029129 http://dx.doi.org/10.1002/hep.32756 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Original Articles: Steatohepatitis Afonso, Marta B. Islam, Tawhidul Magusto, Julie Amorim, Ricardo Lenoir, Véronique Simões, Rui F. Teixeira, José Silva, Liana C. Wendum, Dominique Jéru, Isabelle Vigouroux, Corinne Castro, Rui E. Oliveira, Paulo J. Prip‐Buus, Carina Ratziu, Vlad Gautheron, Jérémie Rodrigues, Cecília M. P. RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease |
title | RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease |
title_full | RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease |
title_fullStr | RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease |
title_full_unstemmed | RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease |
title_short | RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease |
title_sort | ripk3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease |
topic | Original Articles: Steatohepatitis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10026966/ https://www.ncbi.nlm.nih.gov/pubmed/36029129 http://dx.doi.org/10.1002/hep.32756 |
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