Markers of intestinal permeability are already altered in early stages of non-alcoholic fatty liver disease: Studies in children

Background & aims: Recent studies have shown that patients with manifest non-alcoholic fatty liver disease (NAFLD), e.g. steatosis grade 3 or steatohepatitis with or without beginning fibrosis frequently show altered fecal microbiota composition and elevated bacterial endotoxin levels. However, if these alterations are signs of a progressing disease or are already found in initial disease stages has not yet been clarified. Methods: Twenty children with simple steatosis (grade 1) diagnosed by ultrasound and 29 normal weight healthy control children (age <10 years) were included in the study (mean age 7.6 ± 1.1 years). Metabolic parameters, markers of intestinal barrier function and inflammation were determined. Results: Activity of alanine aminotransferase, concentrations of some markers of inflammation and insulin resistance were significantly higher in plasma of NAFLD children than in controls. When compared to controls, plasma bacterial endotoxin and lipopolysaccharide-binding protein (LBP) levels were significantly higher in NAFLD children (+50% and +24%, respectively), while soluble CD14 serum and D-lactate plasma levels as well as the prevalence of small intestinal bacterial overgrowth did not differ between groups. Plasma endotoxin and LBP levels were positive associated with proinflammatory markers like plasminogen activator inhibitor-1, c-reactive protein, interleukin-6 and leptin while no associations with markers of insulin resistance were found. Conclusions: Taken together, our results indicate that even in juvenile patients with early stages of NAFLD e.g. simple steatosis grade 1, plasma endotoxin concentrations are already elevated further suggesting that intestinal barrier dysfunction might be present already in the initial phases of the disease.© 2017 Nier et al

Moderate consumption of fermented alcoholic beverages diminishes diet-induced non-alcoholic fatty liver disease through mechanisms involving hepatic adiponectin signaling in mice

Purpose: Results of some epidemiological studies suggest that moderate alcohol consumption may be associated with a decreased risk to develop NAFLD. Here, the effect of the consumption of moderate beer and diluted ethanol, respectively, on the development of NAFLD were assessed. Methods: Female C57BL/6J mice were fed a control diet (C-D) or a diet rich in fructose, fat and cholesterol (FFC) enriched isocalorically and isoalcoholically with beer (FFC + B) or plain ethanol (FFC + E) (2.5 g ethanol/kg body weight/day) for 7 weeks. Liver damage was assessed by histology using NAFLD activity score. Markers of inflammation, insulin resistance and adiponectin signaling were measured at mRNA and protein levels. Using J774A.1 cells as a model of Kupffer cells, the effect of alcoholic beverages on adiponectin receptor 1 (Adipor1) was assessed. Results: Hepatic triglyceride concentration, neutrophil granulocytes, iNOS protein concentrations and early signs of insulin resistance found in FFC-fed mice were significantly attenuated in FFC+ B-fed mice (P < 0.05 for all). These findings were associated with a super-induction of Adipor1 mRNA expression (+ ~ 18-fold compared to all other groups) and a decrease of markers of lipid peroxidation in liver tissue of FFC + B-fed mice when compared to FFC-fed animals. Similar differences were not found between FFC– and FFC+ E-fed mice. Expression of Adipor1 was also super-induced (7.5-fold) in J774A.1 cells treated with beer (equivalent to 2 mmol/L ethanol). Conclusions: These data suggest that moderate intake of fermented alcoholic beverages such as beer at least partially attenuates NAFLD development through mechanisms associated with hepatic AdipoR1 expression.© The Author(s) 201

Oral arginine supplementation protects female mice from the onset of non-alcoholic steatohepatitis

Dietary arginine (Arg) supplementation has been proposed to have positive effects on the development of liver diseases. In the present study, we investigate if an oral Arg supplementation in diet protects mice fed a fructose, fat and cholesterol enriched Western-style diet (WSD) from the development of non-alcoholic steatohepatitis (NASH). Female C57BL/6J mice were fed a liquid control diet or a liquid WSD ± Arg (2.49 g/kg body weight/day) for 6 weeks. Indices of liver injury, glucose metabolism and intestinal permeability were determined. While Arg supplementation had no effects on body weight gain, fasting blood glucose levels were significantly lower in WSD+Arg-fed mice than in C+Arg-fed animals. WSD-fed mice developed liver steatosis accompanied with inflammation, both being significantly attenuated in WSD+Arg-fed mice. These effects of Arg supplementation went along with a protection against WSD-induced decreased tight junction protein levels in the upper parts of the small intestine, increased levels of bacterial endotoxin in portal plasma as well as increased hepatic toll-like receptor-4 mRNA and 4-hydroxynonenal protein adduct levels. In conclusion, Arg supplementation may protect mice from the development of NASH.© The Author(s