Modulatory Effect of Dihydromyricetin on Chronic Alcoholic Liver Injury Based on the FXR-NLRP3 Signaling Pathway and Serum and Liver Metabolomics.

Background: In modern diets, alcohol consumption has led to an increase in the number of cases of alcohol-related liver disease (ALD). Dihydromyricetin (DMY) is commonly used as a hepatoprotective agent owing to its remarkable efficacy in treating chronic alcoholic liver injury; however, its mechanism of action is unclear. The object of the study is to investigate the effect and mechanism of DMY in alleviating chronic ALD. Methods: A mouse model of chronic ALD was established. Mice were treated with DMY for 56 days, and their biochemical parameters including liver function, blood lipids, and oxidative stress-related indices were measured. Farnesoid X receptor (FXR) expression, NOD-like receptor protein 3 (NLRP3) pathway-related protein expression, and inflammation-related gene expression were determined to elucidate the mechanism of DMY in mice with ALD. Lastly, serum and liver metabolomics-based UHPLC-Orbitrap Exploris MS analyses were used to determine the influence of the metabolism of DMY on mice with ALD. Results: Pharmacodynamic studies showed that DMY could decrease aspartate transaminase, alanine transaminase, triglyceride, and low-density lipoprotein cholesterol levels, improve superoxide dismutase activity, and reduce inflammation in mice with ALD. DMY treatment protects the liver by increasing FXR protein expression and by decreasing NLRP3 pathway-related protein expression and inflammatory gene expression. Metabolomics analysis indicated that ethanol treatment mainly altered metabolism in mice. DMY could regulate 10 metabolites in serum, namely, N-α-acetyllysine, 1-pyrrolinecytosine, glutamyllysine, 5-methylcytosine, N-methylvaline, pyridoxamine, demethoxycurcumin, L-arginine, triacetin, and 15-methylpalmitate. It could also regulate 31 metabolites in the liver, including L-methionine and L-leucine. DMY treatment altered the following important pathways: valine, leucine, and isoleucine biosynthesis; cysteine and methionine metabolism; and valine, leucine, and isoleucine degradation. Correlation analyses using heatmaps revealed that the metabolic parameters are closely related to the pharmacodynamic index. Conclusion: These findings indicated that DMY alleviated ALD by regulating the FXR-NLRP3 signaling pathway and could treat serum and liver metabolic disorders. [ABSTRACT FROM AUTHOR]