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Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with non-alcoholic steatohepatitis
  1. Jef Verbeek1,
  2. Matthias Lannoo2,
  3. Eija Pirinen3,4,
  4. Dongryeol Ryu3,
  5. Pieter Spincemaille5,
  6. Ingrid Vander Elst1,
  7. Petra Windmolders1,
  8. Karin Thevissen5,
  9. Bruno P A Cammue5,6,
  10. Jos van Pelt1,
  11. Sabine Fransis7,
  12. Peter Van Eyken7,
  13. Chantal Ceuterick-De Groote8,
  14. Paul P Van Veldhoven9,
  15. Pierre Bedossa10,
  16. Frederik Nevens1,
  17. Johan Auwerx3,
  18. David Cassiman1,11
  1. 1Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium
  2. 2Department of Abdominal Surgery, University Hospitals KU Leuven, Leuven, Belgium
  3. 3Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
  4. 4Departments of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland
  5. 5Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Leuven, Belgium
  6. 6Department of Plant Systems Biology, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium
  7. 7Department of Pathology, Ziekenhuis Oost-Limburg, Genk, Belgium
  8. 8Laboratory of Ultrastructural Neuropathology, Institute Born-Bunge (IBB), University of Antwerp, Antwerp, Belgium
  9. 9Laboratory of Lipid Biochemistry and Protein Interactions, KU Leuven, Leuven, Belgium
  10. 10Department of Pathology, Hopital Beaujon, Clichy, France
  11. 11Metabolic Center, University Hospitals KU Leuven, Leuven, Belgium
  1. Correspondence to Dr Jef Verbeek, Department of Hepatology, University Hospitals KU Leuven, Herestraat 49, Leuven 3000, Belgium; jef.verbeek{at}uzleuven.be

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.

  • NONALCOHOLIC STEATOHEPATITIS
  • FATTY LIVER
  • OBESITY SURGERY
  • LIVER METABOLISM
  • OXIDATIVE METABOLISM

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