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Ferroptosis mediated by the interaction between Mfn2 and IREα promotes arsenic-induced nonalcoholic steatohepatitis.
- Source :
-
Environmental research [Environ Res] 2020 Sep; Vol. 188, pp. 109824. Date of Electronic Publication: 2020 Jun 23. - Publication Year :
- 2020
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Abstract
- Exposure to arsenic is a risk factor for nonalcoholic steatohepatitis (NASH). Ferroptosis is a form of regulated cell death defined by the accumulation of lipid peroxidation. In the current study, we observed the occurrence of ferroptosis in arsenic-induced NASH by assessing ferroptosis related hallmarks. In vitro, we found that ferrostatin-1 effectively attenuated the executing of ferroptosis and NASH. Simultaneously, the expression of ACSL4 (acyl-CoA synthetase long-chain family member 4) was upregulated in rat's liver and L-02 cells exposed to arsenic. While, suppression of ACSL4 with rosiglitazone or ACSL4 siRNA remarkably alleviated arsenic-induced NASH and ferroptosis through diminishing 5-hydroxyeicosatetraenoic acid (5-HETE) content. Additionally, Mitofusin 2 (Mfn2), a physical tether between endoplasmic reticulum and mitochondria, has rarely been explored in the ferroptosis. Using Mfn2 siRNA or inositol-requiring enzyme 1 alpha (IRE1α) inhibitor, we found NASH and ferroptosis were obviously mitigated through reducing 5-HETE content. Importantly, Co-IP assay indicated that Mfn2 could interact with IRE1α and promoted the production of 5-HETE, ultimately led to ferroptosis and NASH. Collectively, our data showed that ferroptosis is involved in arsenic-induced NASH. These data provide insightful viewpoints into the mechanism of arsenic-induced NASH.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Coenzyme A Ligases
Endoribonucleases drug effects
Endoribonucleases physiology
Ferroptosis
GTP Phosphohydrolases drug effects
GTP Phosphohydrolases physiology
Mitochondrial Proteins drug effects
Mitochondrial Proteins physiology
Multienzyme Complexes drug effects
Multienzyme Complexes physiology
Protein Serine-Threonine Kinases drug effects
Protein Serine-Threonine Kinases physiology
Rats
Arsenic toxicity
Non-alcoholic Fatty Liver Disease chemically induced
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0953
- Volume :
- 188
- Database :
- MEDLINE
- Journal :
- Environmental research
- Publication Type :
- Academic Journal
- Accession number :
- 32593899
- Full Text :
- https://doi.org/10.1016/j.envres.2020.109824