Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with non-alcoholic steatohepatitis. Issue 4 (10th June 2014)

• Record Type: Journal Article
• Authors: Verbeek, Jef; Lannoo, Matthias; Pirinen, Eija; Ryu, Dongryeol; Spincemaille, Pieter; Vander Elst, Ingrid; Windmolders, Petra; Thevissen, Karin; Cammue, Bruno P A; van Pelt, Jos; Fransis, Sabine; Van Eyken, Peter; Ceuterick-De Groote, Chantal; Van Veldhoven, Paul P; Bedossa, Pierre; Nevens, Frederik; Auwerx, Johan; Cassiman, David
• Is Part Of: Gut. Volume 64:Issue 4(2015)
• Page Start: 673
• Page End: 683
• Publication Date: 2014-06-10
• Subjects: NONALCOHOLIC STEATOHEPATITIS -- FATTY LIVER -- OBESITY SURGERY -- LIVER METABOLISM -- OXIDATIVE METABOLISM; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2014-306748
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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-α (TNF-α) 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-α 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-α. These data suggest that modulation of hepatic mitochondrial function contributes to the favourable effect of RYBG on established NASH.