Discovery of lignans as the effective inhibitors of CES1A alleviate lipid droplets formation.

ER carboxylesterase 1A (CES1A) is an important metabolic enzyme involved in lipid metabolism. Targeting the CES1A is a promising approach for diseases associated with disorders of lipid metabolism therapy. In this study, screening of 26 natural lignans, three of them were found displaying potent inhibition on CES1A and high specificity over other serine hydrolases. Inhibition kinetic analyses demonstrated that Schisandrin C and Anwuligan were mixed-type inhibitors, while Magnolol acts as a competitive inhibitor. Further investigation showed that they were cell permeable and exhibited minimal cytotoxicity and mitochondrial toxicity, as well as capable of inhibiting intracellular CES1A in living cells. Further investigation found that three Schisandras decreased the number of lipid droplets (LDs) in free fatty acid (FFA)-treated HepG2 cells. Collectively, our findings suggest that Schisandrin C is a potent and highly selective inhibitor of CES1A, which can be served as a promising lead compound.