Phenotypic and Metabolomic Characteristics of Mouse Models of Diet-Induced Hepatic Steatosis

Abstract

Abstract Background Nonalcoholic steatohepatitis (NASH) is metabolic disease that may progress to cirrhosis and hepatocellular carcinoma. Mouse models of diet-induced NASH, 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 NASH in humans remain to be established. Studies have explored the potential use of serological metabolites as biomarkers of NASH severity in relation to human NASH. Methods We performed a comparative analysis of three mouse models of diet-induced NASH in terms of phenotypic and metabolomic characteristics; NASH 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 NASH was evaluated. Regarding metabolomics, the number of lipoprotein metabolites increased with both diet and NASH 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 NASH 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 NASH and its relevance to human NASH. The observed upregulation of lipoprotein expression reveals a feedforward mechanism for NASH development that may be targeted for the development of noninvasive theranostics.