title: Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with non-alcoholic steatohepatitis.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Verbeek
authors.affiliation: Department of Abdominal Surgery, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lannoo
authors.affiliation: Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Departments of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Pirinen
authors.affiliation: Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Spincemaille
authors.affiliation: Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Vander Elst
authors.affiliation: Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Windmolders
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Thevissen
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Leuven, Belgium Department of Plant Systems Biology, Vlaams Instituut voor Biotechnologie (VIB), Ghent, Belgium.
authors.forename: Bruno P A
authors.initials: BP
authors.lastname: Cammue
authors.affiliation: Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: van Pelt
authors.affiliation: Department of Pathology, Ziekenhuis Oost-Limburg, Genk, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Fransis
authors.affiliation: Department of Pathology, Ziekenhuis Oost-Limburg, Genk, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Eyken
authors.affiliation: Laboratory of Ultrastructural Neuropathology, Institute Born-Bunge (IBB), University of Antwerp, Antwerp, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Ceuterick-De Groote
authors.affiliation: Laboratory of Lipid Biochemistry and Protein Interactions, KU Leuven, Leuven, Belgium.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.affiliation: Department of Pathology, Hopital Beaujon, Clichy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.affiliation: Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium Metabolic Center, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Cassiman
mesh_terms: D000818:Animals; D015390:Gastric Bypass; D006801:Humans; D007333:Insulin Resistance; D008107:Liver Diseases; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000502:physiology*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D014409:Tumor Necrosis Factor-alpha
keywords: FATTY LIVER; LIVER METABOLISM; NONALCOHOLIC STEATOHEPATITIS; OBESITY SURGERY; OXIDATIVE METABOLISM