Abstract
Metabolomic analysis has been used to characterize the effects and mechanisms of drugs for nonalcoholic fatty liver disease (NAFLD) at the metabolic level. Nuciferine is an active component derived from folium nelumbinis and has been demonstrated to have beneficial effects on a high-fat diet (HFD) induced hepatic steatosis model. However, the effect of the altered metabolites of nuciferine on NAFLD has not yet been elucidated. In this study, we established a NAFLD rat model using HFD and treated with nuciferine. The lipid content levels, pro-inflammatory cytokines, and oxidative stress were investigated to access the therapeutic effects of nuciferine. Additionally, the metabolic regulatory mechanisms of nuciferine on NAFLD were analyzed using untargeted metabolomics. Gene expression of the key enzymes related to the changed metabolic pathways following nuciferine intervention was also investigated. The results showed that nuciferine treatment significantly reduced the body weight, levels of lipids, and liver enzymes in the blood and improved the hepatic steatosis in the NAFLD rat model. Nuciferine treatment also increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the levels of methane dicarboxylic aldehyde (MDA) in the liver. Nuciferine treatment decreased the serum levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) and upregulated the gene expression of IL-6, IL-1β, and TNF-α in the liver. Metabolomic analysis indicated a metabolism disorder in the NAFLD rat model reflected in a dysfunction of the glycerophospholipid, linoleic acid, alpha-linolenic acid, arginine and proline metabolism. Conversely, treatment with nuciferine improved the metabolic disorder in the NAFLD rat model. Nuciferine treatment also regulated the gene expression of key enzymes related to the glycerophospholipid, linoleic acid, and alpha-linolenic acid metabolism pathways in the liver. In conclusion, our study demonstrated an amelioration of the metabolic disorders following nuciferine treatment in NAFLD rat model. Our study contributes to the understanding of the effects and mechanisms of drugs for complex diseases using metabolomic analysis and experimental approaches.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disease that is characterized by steatosis of the hepatocytes and dyslipidemia
Consistent with previous studies (Jiang et al, 2016), our results showed that the body weight, lipid contents, and liver enzymes in the serum of animals were increased in rats receiving highfat diet (HFD)
Nuciferine showed a remarkable effect on the nonalcoholic fatty liver disease (NAFLD), reflecting an improvement in hyperlipidemia and liver steatosis in the NAFLD model rats
Summary
Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disease that is characterized by steatosis of the hepatocytes and dyslipidemia. Prolonged NAFLD could cause chronic metabolic diseases, including diabetes, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC) (Wilkins et al, 2013; Masarone et al, 2014). Metabolomics can assist with screening the modifications to the endogenous metabolites in the disease models in order to understand the pathogenesis of diseases at the metabolic level. The dysfunction of the metabolic processes in NAFLD has been reviewed previously (Yu et al, 2017). Silybin could modulate the lipid, polyol, and amino acid metabolisms, as well as the urea and the tricarboxylic acid cycles in a NAFLD mouse model (Sun et al, 2020)
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