Nanoplastic propels diet-induced NAFL to NASH via ER-mitochondrial tether-controlled redox switch
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved..
Nonalcoholic steatohepatitis (NASH) is multifactorial that lifestyle, genetic, and environmental factors contribute to its onset and progression, thereby posing a challenge for therapeutic intervention. Nanoplastic (NP) is emerged as a novel environmental metabolism disruptor but the etiopathogenesis remains largely unknown. In this study, C57BL/6 J mice were fed with normal chow diet (NCD) and high-fat diet (HFD) containing 70 nm polystyrene microspheres (NP). We found that dietary-derived NP adsorbed proteins and agglomerated during the in vivo transportation, enabling diet-induced hepatic steatosis to NASH. Mechanistically, NP promoted liver steatosis by upregulating Fatp2. Furthermore, NP stabilized the Ip3r1, and facilitated ER-mitochondria contacts (MAMs) assembly in the hepatocytes, resulting in mitochondrial Ca2+ overload and redox imbalance. The redox-sensitive Nrf2 was decreased in the liver of NP-exposed mice, which positively regulated miR26a via direct binding to its promoter region [-970 bp to -847 bp and -318 bp to -176 bp]. NP decreased miR26a simultaneously upregulated 10 genes involved in MAMs formation, lipid uptake, inflammation, and fibrosis. Moreover, miR26a inhibition elevated MAMs-tether Vdac1, which promoted the nucleus translocation of NF-κB P65 and Keap1 and functionally inactivated Nrf2, leading to a vicious cycle. Hepatocyte-specific overexpressing miR26a effectively restored ER-mitochondria miscommunication and ameliorated NASH phenotype in NP-exposed and Keap1-overexpressed mice on HFD. The hepatic MAM-tethers/Nrf2/miR26a feedback loop is an essential metabolic switch from simple steatosis to NASH and a promising therapeutic target for oxidative stress-associated liver damage and NASH.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:465 |
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| Enthalten in: |
Journal of hazardous materials - 465(2024) vom: 05. Feb., Seite 133142 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wei, Jie [VerfasserIn] |
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| Links: |
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| Themen: |
Environmental metabolism disruptor/ Ip3r1/ Non‐alcoholic fatty liver disease / Vdac1 /Nrf2 |
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| Anmerkungen: |
Date Completed 08.02.2024 Date Revised 08.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jhazmat.2023.133142 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM365520195 |
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| 100 | 1 | |a Wei, Jie |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Nanoplastic propels diet-induced NAFL to NASH via ER-mitochondrial tether-controlled redox switch |
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| 520 | |a Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a Nonalcoholic steatohepatitis (NASH) is multifactorial that lifestyle, genetic, and environmental factors contribute to its onset and progression, thereby posing a challenge for therapeutic intervention. Nanoplastic (NP) is emerged as a novel environmental metabolism disruptor but the etiopathogenesis remains largely unknown. In this study, C57BL/6 J mice were fed with normal chow diet (NCD) and high-fat diet (HFD) containing 70 nm polystyrene microspheres (NP). We found that dietary-derived NP adsorbed proteins and agglomerated during the in vivo transportation, enabling diet-induced hepatic steatosis to NASH. Mechanistically, NP promoted liver steatosis by upregulating Fatp2. Furthermore, NP stabilized the Ip3r1, and facilitated ER-mitochondria contacts (MAMs) assembly in the hepatocytes, resulting in mitochondrial Ca2+ overload and redox imbalance. The redox-sensitive Nrf2 was decreased in the liver of NP-exposed mice, which positively regulated miR26a via direct binding to its promoter region [-970 bp to -847 bp and -318 bp to -176 bp]. NP decreased miR26a simultaneously upregulated 10 genes involved in MAMs formation, lipid uptake, inflammation, and fibrosis. Moreover, miR26a inhibition elevated MAMs-tether Vdac1, which promoted the nucleus translocation of NF-κB P65 and Keap1 and functionally inactivated Nrf2, leading to a vicious cycle. Hepatocyte-specific overexpressing miR26a effectively restored ER-mitochondria miscommunication and ameliorated NASH phenotype in NP-exposed and Keap1-overexpressed mice on HFD. The hepatic MAM-tethers/Nrf2/miR26a feedback loop is an essential metabolic switch from simple steatosis to NASH and a promising therapeutic target for oxidative stress-associated liver damage and NASH | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Wang, Huan |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Ni, Xiuye |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Yilong |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Jingru |e verfasserin |4 aut | |
| 700 | 1 | |a You, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Lei, Zhao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Heqing |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Yi |e verfasserin |4 aut | |
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