Abstract
BackgroundDietary 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.MethodsMale 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.ResultsDietary 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.ConclusionsDietary intervention, and not losartan, completely restores the metabolic phenotype in a representative mouse model with pre-existent NASH, obesity, insulin resistance and hypercholesterolemia.
Highlights
Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment
Mice were fed a ‘Western’ high fat-high sucrose diet (HF-HSD) with 44.6% of kcal derived from fat and 40.6% of kcal derived from carbohydrates (TD.08811, 45%kcal Fat Diet, Harlan Laboratories Inc., Madison, WI, USA) or a normal chow diet (NCD) (V1534-000 ssniff R/M-H, ssniff Spezialdiäten GmbH, Soest, Germany)
Insulin resistance and hypercholesterolemia Mice in which the HF-HSD was switched to NCD (Return to NCD), displayed a normalization of body weight (Fig. 2a) and epididymal fat pad weight (Fig. 2b)
Summary
Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment. Histological evidence of its efficacy is limited and its impact on hepatic pathways involved in NASH is underreported. We evaluated the effect of dietary intervention versus losartan on NASH and associated systemic metabolic features in a representative mouse model. Due to its strong pathophysiological and epidemiological association with obesity, insulin resistance, dyslipidemia and hypertension, NAFLD is considered as the hepatic manifestation of the metabolic syndrome [2]. NAFLD is the collective noun for a spectrum of histological abnormalities ranging from isolated steatosis to nonalcoholic steatohepatitis (NASH). The latter is characterized by steatosis, hepatocyte ballooning and inflammation with or without fibrosis [3]. NASH is the most rapidly rising indication for liver transplantation [5, 6]
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