Hyperoside modulates bile acid and fatty acid metabolism, presenting a potentially promising treatment for non-alcoholic fatty liver disease

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial chronic condition that requires a systematic approach for effective management. Multi-effect therapeutic drugs derived from traditional Chinese medicine are increasingly being recognized as promising alternatives for NAFLD intervention. Hyperoside, a natural flavone glycoside found in Cuscuta chinensis Lam, Forsythia suspensa, and Crataegus pinnatifida Bge, has been shown to effectively mitigate NAFLD in rats. However, the underlying mechanism through which hyperoside alleviates NAFLD remains unclear. OBJECTIVE: This study aims to explore the specific mechanisms by which hyperoside intervenes in the progression of NAFLD. METHODS: In this study, a high-fat diet was used to induce the NAFLD model in rats. An integrated analysis, including mass spectrometry-based lipidomics, TMT-based proteomics, 16S rRNA sequencing, and bile acid-targeted metabolomics, was employed to identify significantly altered metabolites and proteins. Western blotting, molecular docking, and isothermal titration calorimetry were conducted to analyze the direct targets of action. RESULTS: The results indicate that hyperoside activates farnesoid X receptor (FXR), promoting fatty acid oxidation and the efflux of bile acids from the liver. Additionally, hyperoside inhibits hepatic ATP citrate lyase (ACLY) and works synergistically with activated FXR to suppress de novo lipogenesis. Hyperoside also inhibits intestinal microbes linked to bile-salt hydrolase (BSH) activity, which enhances the production of ileal bile acids (BAs), particularly conjugated BAs, thus reducing the liver toxicity of endogenous BAs. CONCLUSION: Our findings suggest that hyperoside alleviates NAFLD by modulating fatty acid and bile acid metabolism through FXR and ACLY, suggesting its potential as a multi-effect candidate drug for the treatment of NAFLD.