Marine n-3 Polyunsaturated Fatty Acids Alleviate Metabolic Dysfunction-Associated Fatty Liver Disease Through Adiponectin-Ceramide Axis

Metabolic dysfunction-associated fatty liver disease (MAFLD), characterized as hepatic triglyceride accumulation, affects a quarter of the adult population worldwide, but limited therapeutic approaches are available in the treatment of MAFLD. It is widely believed that marine n-3 polyunsaturated fatty acids (PUFA) intervention could ameliorate MAFLD, however, the underlying mechanism remains elusive. Herein, in a case-control study, we identified serum C16:0-ceramide as a biomarker indicating MAFLD patients, which was negatively associated with n-3 PUFA levels in red blood cell phospholipids. The causality was confirmed by a randomized controlled trial (RCT), highlighting that supplemental n-3 PUFA had notable action in lowering serum C16:0-ceramide concentrations. The RCT indicated that serum adiponectin levels were negatively associated with serum C16:0-ceramide levels. An MAFLD model was established in mice fed a high-fat, high-cholesterol diet, and administration of n-3 PUFA increased adiponectin secretion and decreased hepatic C16:0-ceramide concentrations associated with reduced hepatic steatosis. In these mice, adiponectin administration contributed to decreased hepatic C16:0-ceramide concentrations and alleviated hepatic triglyceride accumulation through reduced de novo fatty acid synthesis and increased fatty acid β-oxidation. Furthermore, administration of C16:0-ceramide reversed the beneficial effects of n-3 PUFA in high-fat diet-induced MAFLD. This work reveals a novel mechanism, namely adiponectin-C16:0-ceramide axis, through which n-3 PUFA play a notable role in ameliorating MAFLD.