Conclusion
Our study deciphers the structural features of silybin contributing to hepatic lipid remodeling and suggests that silymarin/silybin protects the liver in individuals with mild metabolic dysregulation, involving a lipid class switch from triglycerides to phospholipids, whereas it may be less effective in disease states associated with severe metabolic dysregulation.
Methods
Experiments were performed with hepatocyte cell lines and primary monocytes in vitro under both basal and stressed conditions, and in mice in vivo. Quantitative lipidomics was used to detect changes in phospholipids and triglycerides. Key findings were confirmed by Western blotting, quantitative PCR, microscopy, enzyme activity assays, metabolic flux studies, and functional relationships were investigated using selective inhibitors.
Results
We show that specifically the stereoisomer silybin A decreases triglyceride levels and lipid droplet content, while enriching major phospholipid classes and maintaining a homeostatic phospholipid composition in human hepatocytes in vitro and in mouse liver in vivo under normal and pre-disease conditions. Conversely, in cell-based disease models of lipid overload and lipotoxic stress, silybin treatment primarily depletes triglycerides. Mechanistically, silymarin/silybin suppresses phospholipid-degrading enzymes, induces phospholipid biosynthesis to varying degrees depending on the conditions, and down-regulates triglyceride remodeling/biosynthesis, while inducing complex changes in sterol and fatty acid metabolism. Structure-activity relationship studies highlight the importance of the 1,4-benzodioxane ring configuration of silybin A in triglyceride reduction and the saturated 2,3-bond of the flavanonol moiety in phospholipid accumulation. Enrichment of hepatic phospholipids and intracellular membrane expansion are associated with a heightened biotransformation capacity.