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Title
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Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with non-alcoholic steatohepatitis
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Author
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Abstract
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| Objective No therapy for non-alcoholic steatohepatitis (NASH) has been approved so far. Roux-en-y gastric bypass (RYGB) is emerging as a therapeutic option, although its effect on NASH and related hepatic molecular pathways is unclear from human studies. We studied the effect of RYGB on pre-existent NASH and hepatic mitochondrial dysfunction-a key player in NASH pathogenesis-in a novel diet-induced mouse model nicely mimicking human disease. Design C57BL/6J mice were fed a high-fat high-sucrose diet (HF-HSD). Results HF-HSD led to early obesity, insulin resistance and hypercholesterolaemia. HF-HSD consistently induced NASH (steatosis, hepatocyte ballooning and inflammation) with fibrosis already after 12-week feeding. NASH was accompanied by hepatic mitochondrial dysfunction, characterised by decreased mitochondrial respiratory chain (MRC) complex I and IV activity, ATP depletion, ultrastructural abnormalities, together with higher 4-hydroxynonenal (HNE) levels, increased uncoupling protein 2 (UCP2) and tumour necrosis factor-alpha (TNF-alpha) mRNA and free cholesterol accumulation. In our model of NASH and acquired mitochondrial dysfunction, RYGB induced sustained weight loss, improved insulin resistance and inhibited progression of NASH, with a marked reversal of fibrosis. In parallel, RYGB preserved hepatic MRC complex I activity, restored ATP levels, limited HNE production and decreased TNF-a mRNA. Conclusions Progression of NASH and NASH-related hepatic mitochondrial dysfunction can be prevented by RYGB. RYGB preserves respiratory chain complex activity, thereby restoring energy output, probably by limiting the amount of oxidative stress and TNF-alpha. These data suggest that modulation of hepatic mitochondrial function contributes to the favourable effect of RYBG on established NASH. |
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Language
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English
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Source (journal)
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Gut : the journal of the British Society for Gastroenterology / British Society for Gastroenterology. - London, 1960, currens
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Publication
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London
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2015
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ISSN
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0017-5749
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DOI
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10.1136/GUTJNL-2014-306748
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Volume/pages
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64
:4
(2015)
, p. 673-683
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ISI
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000350800100023
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Pubmed ID
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24917551
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Full text (Publisher's DOI)
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Full text (open access)
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