A metabolomics and proteomics-based study on the metabolic effects of arecoline on the liver

Arecoline is one of the primary constituents of the areca nut. Its pharmacological effects include analgesia, anti-inflammation, and anti-allergy. Current researches on the toxicity of arecoline mainly focuse on oral carcinogenesis and immunotoxicity, so there are relatively little systematic study on its hepatotoxicity and underlying mechanisms. Therefore, this study aims to explore the mechanisms of hepatotoxicity induced by different doses of arecoline in mice by integrating metabolomics and proteomics. In our pathological results, we found that the medium and high dose groups of arecoline can cause fatty degeneration in the livers of mice. Additionally, the different doses of arecoline increased the levels of ALT and AST in the serum of mice. Proteomics research identified that exposure to different doses of arecoline primarily affected the PPARs signaling pathway, thereby influencing fatty acid metabolism, amino acid metabolism, and arachidonic acid metabolism pathways. Metabolomics research identified differential metabolites in each group after arecoline exposure. We observed that with increasing doses of arecoline, the metabolites of lipids and lipid-like molecules in mice gradually increased. The results suggested arecoline may induce fatty degeneration in the liver of mice through the PPARα/Acox-1 mediated pathways of oxidative stress, inflammatory response, energy, and lipid metabolism.