RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
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 γ (PPARγ) was increased in Ripk3-/- mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:70 |
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| Enthalten in: |
Gut - 70(2021), 12 vom: 24. Dez., Seite 2359-2372 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Afonso, Marta B [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.01.2022 Date Revised 12.01.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1136/gutjnl-2020-321767 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM319256693 |
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| 100 | 1 | |a Afonso, Marta B |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease |
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| 500 | |a Date Completed 12.01.2022 | ||
| 500 | |a Date Revised 12.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 γ (PPARγ) was increased in Ripk3-/- mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a cell death | |
| 650 | 4 | |a chronic liver disease | |
| 650 | 4 | |a lipid metabolism | |
| 650 | 4 | |a molecular carcinogenesis | |
| 650 | 4 | |a nonalcoholic steatohepatitis | |
| 650 | 7 | |a Biomarkers |2 NLM | |
| 650 | 7 | |a RIPK3 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Receptor-Interacting Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 700 | 1 | |a Rodrigues, Pedro M |e verfasserin |4 aut | |
| 700 | 1 | |a Mateus-Pinheiro, Miguel |e verfasserin |4 aut | |
| 700 | 1 | |a Simão, André L |e verfasserin |4 aut | |
| 700 | 1 | |a Gaspar, Maria M |e verfasserin |4 aut | |
| 700 | 1 | |a Majdi, Amine |e verfasserin |4 aut | |
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| 700 | 1 | |a Alonso, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Santos-Laso, Alvaro |e verfasserin |4 aut | |
| 700 | 1 | |a Jimenez-Agüero, Raul |e verfasserin |4 aut | |
| 700 | 1 | |a Eizaguirre, Emma |e verfasserin |4 aut | |
| 700 | 1 | |a Bujanda, Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Pareja, Maria Jesus |e verfasserin |4 aut | |
| 700 | 1 | |a Banales, Jesus M |e verfasserin |4 aut | |
| 700 | 1 | |a Ratziu, Vlad |e verfasserin |4 aut | |
| 700 | 1 | |a Gautheron, Jeremie |e verfasserin |4 aut | |
| 700 | 1 | |a Castro, Rui E |e verfasserin |4 aut | |
| 700 | 1 | |a Rodrigues, Cecília M P |e verfasserin |4 aut | |
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