TY - JOUR
T1 - Dietary intervention, but not losartan, completely reverses non-alcoholic steatohepatitis in obese and insulin resistant mice
AU - Verbeek, Jef
AU - Spincemaille, Pieter
AU - Vanhorebeek, Ilse
AU - Van den Berghe, Greet
AU - Vander Elst, Ingrid
AU - Windmolders, Petra
AU - van Pelt, Jos
AU - van der Merwe, Schalk
AU - Bedossa, Pierre
AU - Nevens, Frederik
AU - Cammue, Bruno
AU - Thevissen, Karin
AU - Cassiman, David
PY - 2017/2/23
Y1 - 2017/2/23
N2 - 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.
AB - 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.
KW - NASH
KW - treatment
KW - Diet
KW - Losartan
KW - Angiotensin
KW - FATTY LIVER-DISEASE
KW - II RECEPTOR BLOCKADE
KW - LIFE-STYLE
KW - WEIGHT-LOSS
KW - SCORING SYSTEM
KW - FIBROSIS
KW - NAFLD
KW - TRANSPLANTATION
KW - INFLAMMATION
U2 - 10.1186/s12944-017-0432-7
DO - 10.1186/s12944-017-0432-7
M3 - Article
SN - 1476-511X
VL - 16
JO - Lipids in Health and Disease
JF - Lipids in Health and Disease
M1 - 46
ER -