title: Dietary intervention, but not losartan, completely reverses non-alcoholic steatohepatitis in obese and insulin resistant mice.
abstract: BACKGROUND
  Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment. However, histological evidence of its efficacy is limited and its impact on hepatic pathways involved in NASH is underreported. The efficacy of the angiotensin receptor type 1 blocker losartan is controversial because of varying results in a few animal and human studies. We evaluated the effect of dietary intervention versus losartan on NASH and associated systemic metabolic features in a representative mouse model.
  
  
  METHODS
  Male C57BL/6 J mice with high fat-high sucrose diet (HF-HSD) induced NASH, obesity, insulin resistance and hypercholesterolemia were subjected to dietary intervention (switch from HF-HSD to normal chow diet (NCD)) (n = 9), continuation HF-HSD together with losartan (30 mg/kg/day) (n = 9) or continuation HF-HSD only (n = 9) for 8 weeks. 9 mice received NCD during the entire experiment (20 weeks). We assessed the systemic metabolic effects and performed a detailed hepatic histological and molecular profiling. A P-value of < 0.05, using the group with continuation of HF-HSD only as control, was considered as statistically significant.
  
  
  RESULTS
  Dietary intervention normalized obesity, insulin resistance, and hypercholesterolemia (for all P < 0.001), and remarkably, completely reversed all histological features of pre-existent NASH (for all P < 0.001), including fibrosis measured by quantification of collagen proportional area (P < 0.01). At the hepatic molecular level, dietary intervention targeted fibrogenesis with a normalization of collagen type I alpha 1, transforming growth factor β1, tissue inhibitor of metalloproteinase 1 mRNA levels (for all P < 0.01), lipid metabolism with a normalization of fatty acid translocase/CD36, fatty acid transport protein 5, fatty acid synthase mRNA levels (P < 0.05) and markers related to mitochondrial function with a normalization of hepatic ATP content (P < 0.05) together with sirtuin1 and uncoupling protein 2 mRNA levels (for both P < 0.001). Dietary intervention abolished p62 accumulation (P < 0.01), suggesting a restoration of autophagic flux. Losartan did not significantly affect obesity, insulin resistance, hypercholesterolemia or any histological NASH feature.
  
  
  CONCLUSIONS
  Dietary intervention, and not losartan, completely restores the metabolic phenotype in a representative mouse model with pre-existent NASH, obesity, insulin resistance and hypercholesterolemia.
authors.affiliation: Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium. jef.verbeek@mumc.nl.|Division of Gastroenterology & Hepatology, Department of Internal Medicine, Maastricht University Medical Center, PO box 5800, 6202 AZ, Maastricht, The Netherlands. jef.verbeek@mumc.nl.
authors.forename: Jef
authors.identifier: http://orcid.org/0000-0002-1549-8003
authors.initials: J
authors.lastname: Verbeek
authors.affiliation: Department of Laboratory Medicine, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Spincemaille
authors.affiliation: Clinical Department and Laboratory of Intensive Care Medicine, Division Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Vanhorebeek
authors.affiliation: Clinical Department and Laboratory of Intensive Care Medicine, Division Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
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: Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: van Pelt
authors.affiliation: Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
authors.forename: Schalk
authors.initials: S
authors.lastname: van der Merwe
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: 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
authors.initials: B
authors.lastname: Cammue
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Thevissen
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: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression; D007333:Insulin Resistance; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000178:diet therapy*; D009765:Obesity / Q000178:diet therapy* / Q000188:drug therapy; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D018955:CD36 Antigens; C000716127:COL1A1 protein, human; D000090602:Collagen Type I, alpha 1 Chain; D051780:Sterol Regulatory Element Binding Protein 1; D019808:Losartan
keywords: Angiotensin; Diet; Losartan; NASH; treatment