Dietary Intervention Accelerates NASH Resolution Depending on Inflammatory Status with Minor Additive Effects on Hepatic Injury by Vitamin E Supplementation

Abstract

Despite the lack of effective pharmacotherapy against nonalcoholic steatohepatitis (NASH) and liver fibrosis, vitamin E (vitE) supplementation and lifestyle modifications are recommended for the management of NASH due to promising clinical results. We recently reported a positive effect of supplementation with 800 IU vitE and atorvastatin on NASH resolution in guinea pigs. In the present study, we investigated the effect of high-dose vitE therapy combined with dietary intervention against progressive NASH and advanced fibrosis in the guinea pig model. Sixty-six guinea pigs received either high-fat (HF) or standard guinea pig chow diet (Control) for 25 weeks. Prior to eight weeks of intervention, HF animals were allocated into groups; dietary intervention (Chow) or dietary intervention with 2000 IU/d vitE supplementation (CvitE). Both Chow and CvitE reduced dyslipidemia, hepatic lipid accumulation and liver weight (p < 0.05), while CvitE further decreased hepatocellular ballooning (p < 0.05). Subanalyses of individual responses within intervention groups showed significant correlation between the hepatic hallmarks of NASH and lipid accumulation vs. inflammatory state (p < 0.05). Collectively, our results indicate that individual differences in sensitivity towards intervention and inflammatory status determine the potential beneficial effect of dietary intervention and high-dose vitE supplementation. Moreover, the study suggests that inflammation is a primary target in NASH treatment.

Differential Effects of Dietary Components on Glucose Intolerance and Non-Alcoholic Steatohepatitis

“…Consequently, the starch content of control diets applied in preclinical modeling might induce a metabolic state with little relevance to a healthy human control and—unintentionally—reduce the value of comparisons. For the guinea pig NAFLD/NASH model, a low-fat high-starch (LF-HSt) diet promotes a healthy liver phenotype, however guinea pigs do not display differences in weight or glucose tolerance compared to a HFD [ 26 , 27 , 28 , 29 , 30 ]. To investigate putative differences in a more metabolically relevant control group, a diet low in fat and starch was included (LF-LSt).…”

The effect of acetylsalicylic acid and pentoxifylline in guinea pigs with non‐alcoholic steatohepatitis

“…This ensured that treatment effects were only investigated in animals with fatty livers, more closely mimicking a clinical setting, but also reducing group sizes, which in turn decreased statistical power. We have recently reported differences in sensitivity to diet and vitamin E intervention in NASH guinea pigs, suggesting the presence of high and low responders when investigating effects, for example on inflammatory markers in NASH 19 . This could have contributed to increased variability within groups and potentially underestimated a statistically significant effect of treatment in the present study.…”

“…The guinea pig is a well‐validated model of NASH that develops advanced (F3) fibrosis when fed a human‐like “Western diet” enabling the study of this critical NASH end‐point 13–15,18,19,24 . Accordingly, high‐fat‐fed guinea pigs developed NASH with steatosis, inflammation, ballooning and fibrosis prior to intervention.…”

“…Dietary compositions were similar to previously described 14 . As previously shown, guinea pigs develop NASH with fibrosis following 16 weeks of high‐fat feeding and proceed to develop advanced hepatic fibrosis by week 25‐35 13,14,18,19 . Thus, after 16 weeks, six animals from the high‐fat diet group (HFD pre‐intervention) were randomly selected for baseline euthanasia.…”

The role of biofactors in the prevention and treatment of age‐related diseases

“…Besides targeting steatosis, αT has also been investigated in models of more advanced forms of NAFLD. In a dietary NASH model in guinea pigs, αT (1125 mg/kg diet for 8 weeks) supplementation was able to reduce hepatocyte ballooning while not affecting inflammation or fibrosis 137 . Integrity of the gut barrier and translocation of bacterial products are believed to be associated with the progression of steatosis to NASH 138 .…”