Phenotypic and metabolomic characteristics of mouse models of metabolic associated steatohepatitis
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Published:2024-01-09
Issue:1
Volume:12
Page:
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ISSN:2050-7771
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Container-title:Biomarker Research
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language:en
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Short-container-title:Biomark Res
Author:
Yang Cian-Ru,Lin Wen-Jen,Shen Pei-Chun,Liao Pei-Yin,Dai Yuan-Chang,Hung Yao-Ching,Lai Hsueh‐Chou,Mehmood Shiraz,Cheng Wei-Chung,Ma Wen-Lung
Abstract
Abstract
Background
Metabolic associated steatohepatitis (MASH) is metabolic disease that may progress to cirrhosis and hepatocellular carcinoma. Mouse models of diet-induced MASH, which is characterized by the high levels of fats, sugars, and cholesterol in diets, are commonly used in research. However, mouse models accurately reflecting the progression of MASH in humans remain to be established. Studies have explored the potential use of serological metabolites as biomarkers of MASH severity in relation to human MASH.
Methods
We performed a comparative analysis of three mouse models of diet-induced MASH in terms of phenotypic and metabolomic characteristics; MASH was induced using different diets: a high-fat diet; a Western diet; and a high-fat, high-cholesterol diet. Liver cirrhosis was diagnosed using standard clinical approaches (e.g., METAVIR score, hyaluronan level, and collagen deposition level). Mouse serum samples were subjected to nuclear magnetic resonance spectroscopy–based metabolomic profiling followed by bioinformatic analyses. Metabolomic analysis of a retrospective cohort of patients with hepatocellular carcinoma was performed; the corresponding cirrhosis scores were also evaluated.
Results
Using clinically relevant quantitative diagnostic methods, the severity of MASH was evaluated. Regarding metabolomics, the number of lipoprotein metabolites increased with both diet and MASH progression. Notably, the levels of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) significantly increased with fibrosis progression. During the development of diet-induced MASH in mice, the strongest upregulation of expression was noted for VLDL receptor. Metabolomic analysis of a retrospective cohort of patients with cirrhosis indicated lipoproteins (e.g., VLDL and LDL) as predominant biomarkers of cirrhosis.
Conclusions
Our findings provide insight into the pathophysiology and metabolomics of experimental MASH and its relevance to human MASH. The observed upregulation of lipoprotein expression reveals a feedforward mechanism for MASH development that may be targeted for the development of noninvasive diagnosis.
Funder
China Medical University, Taiwan
Ministry of Science and Technology, Taiwan
Asia University Hospital
China Medical University Hospital
National Science and Technology Council
National Health Research Institutes
Publisher
Springer Science and Business Media LLC
Subject
Biochemistry (medical),Clinical Biochemistry,Molecular Medicine