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New aspects characterizing nonobese NAFLD by the analysis of the intestinal flora and metabolites using a mouse model

ABSTRACT:

Nonalcoholic fatty liver disease (NAFLD) is a major public health problem due to the high incidence affecting approximately one-third of the world’s population. NAFLD is usually linked to obesity and excessive weight. A subset of patients with NAFLD express normal or low body mass index; thus, the condition is called nonobese NAFLD or lean NAFLD. However, patients and healthcare professionals have little awareness and understanding of NAFLD in nonobese individuals. Furthermore, preclinical results from nonobese animal models with NAFLD are unclear. Gut microbiota and their metabolites in nonobese/lean NAFLD patients differ from those in obese NAFLD patients. Therefore, we analyzed the biochemical indices, intestinal flora and intestinal metabolites in a nonobese NAFLD mouse model established using a methionine-choline deficient (MCD) diet. The significantly lean MCD mice had a remarkable fatty liver with lower serum triglyceride and free fatty acid levels as well as higher alanine transaminase and aspartate transaminase levels than normal mice. 16s RNA sequencing of fecal DNA showed that the overall richness and diversity of the intestinal flora decreased in MCD mice, whereas the Firmicutes/Bacteroidota ratio was increased. g_Tuzzerella, s_Bifidobacterium pseudolongum and s_Faecalibaculum rodentium were the predominant species in nonobese NAFLD mice. Fecal metabolomics using LC-MS/MS revealed the potential biomarkers for the prognosis and diagnosis of nonobese NAFLD, including high levels of tyramine glucuronide, 9,12,13-TriHOME and pantetheine 4'-phosphate, and low levels of 3-carbamoyl-2-phenylpropionaldehyde, N-succinyl-L,L-2,6-diaminopimelate, 4-methyl-5-thiazoleethanol, homogentisic acid and estriol. Our findings could be useful to identify and develop drugs to treat nonobese NAFLD and lean NAFLD.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS9365 | MetaboLights | 2024-02-27

REPOSITORIES: MetaboLights

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New aspects characterizing non-obese NAFLD by the analysis of the intestinal flora and metabolites using a mouse model.

Zhang Wenji W Cheng Wenli W Li JingHui J Huang Zhenrui Z Lin Hui H Zhang Wenjuan W

mSystems 20240229 3

Non-alcoholic fatty liver disease (NAFLD) is a major public health problem due to the high incidence affecting approximately one-third of the world's population. NAFLD is usually linked to obesity and excessive weight. A subset of patients with NAFLD expresses normal or low body mass index; thus, the condition is called non-obese NAFLD or lean NAFLD. However, patients and healthcare professionals have little awareness and understanding of NAFLD in non-obese individuals. Furthermore, preclinical ...[more]

PMID: 38421203

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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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