Dietary intervention, but not losartan, completely reverses non-alcoholic steatohepatitis in obese and insulin resistant mice

Jef Verbeek*, Pieter Spincemaille, Ilse Vanhorebeek, Greet Van den Berghe, Ingrid Vander Elst, Petra Windmolders, Jos van Pelt, Schalk van der Merwe, Pierre Bedossa, Frederik Nevens, Bruno Cammue, Karin Thevissen, David Cassiman

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Web of Science)

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 beta 1, 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.

Original languageEnglish
Article number46
Number of pages10
JournalLipids in Health and Disease
Volume16
DOIs
Publication statusPublished - 23 Feb 2017

Keywords

  • NASH
  • treatment
  • Diet
  • Losartan
  • Angiotensin
  • FATTY LIVER-DISEASE
  • II RECEPTOR BLOCKADE
  • LIFE-STYLE
  • WEIGHT-LOSS
  • SCORING SYSTEM
  • FIBROSIS
  • NAFLD
  • TRANSPLANTATION
  • INFLAMMATION

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