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| dc.contributor.author | von Montfort, Claudia |
|---|---|
| dc.contributor.author | Matias, Núria |
| dc.contributor.author | Fernandez, Anna |
| dc.contributor.author | Fucho Salvador, Raquel |
| dc.contributor.author | Conde de la Rosa, Laura |
| dc.contributor.author | Martínez Chantar, Maria Luz |
| dc.contributor.author | Mato, José M. |
| dc.contributor.author | Machida, Keigo |
| dc.contributor.author | Tsukamoto, Hidekazu |
| dc.contributor.author | Murphy, Michael P. |
| dc.contributor.author | Mansouri, Abdellah |
| dc.contributor.author | Kaplowitz, Neil |
| dc.contributor.author | Garcia-Ruiz, Carmen |
| dc.contributor.author | Fernández-Checa Torres, José Carlos |
| dc.date | 2019-02-12T13:59:31Z |
| dc.date | 2019-02-12T13:59:31Z |
| dc.date | 2012-10 |
| dc.date | 2019-02-12T13:59:31Z |
| dc.identifier | 0168-8278 |
| dc.identifier | 642116 |
| dc.identifier | 22687340 |
| dc.identifier.uri | http://hdl.handle.net/2445/128172 |
| dc.description | BACKGROUND & AIMS: Steatohepatitis (SH) is associated with mitochondrial dysfunction and excessive production of superoxide, which can then be converted into H(2)O(2) by SOD2. Since mitochondrial GSH (mGSH) plays a critical role in H(2)O(2) reduction, we explored the interplay between superoxide, H(2)O(2), and mGSH in nutritional and genetic models of SH, which exhibit mGSH depletion. METHODS: We used isolated mitochondria and primary hepatocytes, as well as in vivo SH models showing mGSH depletion to test the consequences of superoxide scavenging. RESULTS: In isolated mitochondria and primary hepatocytes, superoxide scavenging by SOD mimetics or purified SOD decreased superoxide and peroxynitrite generation but increased H(2)O(2) following mGSH depletion, despite mitochondrial peroxiredoxin/thioredoxin defense. Selective mGSH depletion sensitized hepatocytes to cell death induced by SOD mimetics, and this was prevented by RIP1 kinase inhibition with necrostatin-1 or GSH repletion with GSH ethyl ester (GSHee). Mice fed the methionine-choline deficient (MCD) diet or MAT1A(-/-) mice exhibited reduced SOD2 activity; in vivo treatment with SOD mimetics increased liver damage, inflammation, and fibrosis, despite a decreased superoxide and 3-nitrotyrosine immunoreactivity, effects that were ameliorated by mGSH replenishment with GSHee, but not NAC. As a proof-of-principle of the detrimental role of superoxide scavenging when mGSH was depleted transgenic mice overexpressing SOD2 exhibited enhanced susceptibility to MCD-mediated SH. CONCLUSIONS: These findings underscore a critical role for mGSH in the therapeutic potential of superoxide scavenging in SH, and suggest that the combined approach of superoxide scavenging with mGSH replenishment may be important in SH. |
| dc.format | 8 p. |
| dc.format | application/pdf |
| dc.language | eng |
| dc.publisher | Elsevier |
| dc.relation | Versió postprint del document publicat a: https://doi.org/10.1016/j.jhep.2012.05.024 |
| dc.relation | Journal of Hepatology, 2012, vol. 54, num. 4, p. 852-859 |
| dc.relation | https://doi.org/10.1016/j.jhep.2012.05.024 |
| dc.rights | (c) Elsevier, 2012 |
| dc.rights | info:eu-repo/semantics/openAccess |
| dc.subject | Malalties del fetge |
| dc.subject | Estrès oxidatiu |
| dc.subject | Mitocondris |
| dc.subject | Liver diseases |
| dc.subject | Oxidative stress |
| dc.subject | Mitochondria |
| dc.title | Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis |
| dc.type | info:eu-repo/semantics/article |
| dc.type | info:eu-repo/semantics/acceptedVersion |
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