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Dietary amino acid source elicits sex-specific metabolic response to diet-induced NAFLD in murine model.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, we assess the metabolic and hepatic effects of dietary amino acid (AA) source in Western diet (WD)-induced NAFLD in male and female mice. The AA source was either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein-based WD displayed glucose intolerance, fasting hyperglycemia, and insulin-resistance and developed NAFLD associated with changes in hepatic gene expression and dysbiosis. In contrast, males fed the AA-based WD showed no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein-based WD. Females were protected against WD-induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source. Thus, free dietary AA intake prevents the unhealthy metabolic outcomes of a WD in a sex-specific manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE234591 | GEO | 2024/01/01

REPOSITORIES: GEO

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Project description:Background & Aims: Overnutrition is one of the major causes of non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH). Besides the quantity of consumed calories, distinct dietary components are increasingly recognized as important contributor to the pathogenesis of NASH. We aimed to develop and characterize a hitherto missing murine model which resembles both the pathology and nutritional situation of NASH-patients in Western societies. Methods: We developed a NASH-inducing diet (ND) enriched with sucrose, cholesterol and a high concentration of fats rich in saturated fatty acids in a composition which mimics Western food. C57Bl6/N mice were fed with the ND or control chow for 12 weeks. Biochemical, real-time polymerase chain reaction, Western Blot and immunohistochemical analyses were performed to characterize systemic and hepatic changes induced by ND-feeding. Immunohistochemistry was used to assess c-Jun levels and activation in 110 human NAFLD and control liver specimens applying tissue micro array technology. Results: ND-fed mice showed significant body weight gain, impaired glucose tolerance, elevated fasting blood glucose levels as well as decreased adiponectin and increased leptin serum levels compared to control mice. In the liver, ND-feeding led to marked steatosis, enhanced cholesterol levels, distinct signs of oxidative stress, hepatocellular damage, inflammation, activation of hepatic stellate cells, and beginning fibrosis. Transcriptome-wide hepatic gene expression analysis comparing ND-fed mice and control mice indicated main alterations in lipid metabolism and inflammatory processes. Search for over-represented transcription factor target sites among the differentially expressed genes identified AP-1 as the most likely factor to cause the transcriptional changes in ND-livers. Combining differentially expressed gene and protein-protein interaction network analysis identified c-Jun (a component of the AP-1 complex) as hub in the largest connected deregulated sub-network in ND-livers. In accordance, ND-livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun RNA and protein expression was enhanced in ND-fed compared to control mice. Also NAFLD-patients showed enhanced hepatic c-Jun levels, which correlated with inflammation, and notably, with the degree of hepatic steatosis. Conclusions: The new dietary mouse-model shows important pathological changes also found in human NASH and indicates c-jun/AP-1 activation as critical regulator of hepatic alterations. Abundance of c-jun in NAFLD likely facilitates development and progression of NASH, and thus, c-jun appears as attractive prognostic and therapeutic target of NAFLD progression. 14-weeks old male C57BL/6N mice were fed with either regular diet or a newly designed NASH-inducing diet for 12 weeks. Hepatic gene expression levels were measured thereafter.

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Dietary amino acid source elicits sex-specific metabolic response to diet-induced NAFLD in murine model.

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