n-3 Polyunsaturated Fatty Acids Mediate Hyodeoxycholic Acid-FXR Signaling to Ameliorate Metabolic Dysfunction-associated Fatty Liver Disease.

Accumulating evidence has shown that n-3 polyunsaturated fatty acids (PUFA) intervention contributes to ameliorating metabolic dysfunction-associated fatty liver disease (MAFLD); however, the underlying mechanism through which n-3 PUFA alleviate MAFLD remains elusive. Critical gut microbiota-modified metabolites and host targets have been implicated in the initiation and development of MAFLD. Here, a case-control study was performed which indicated that gut microbiota-modified bile acids, notably serum hydeoxycholic acid (HDCA) species, were significantly lower in MAFLD subjects compared with the healthy controls and were negatively associated with n-3 PUFA proportions in red blood phospholipids, suggesting a link between n-3 PUFA, HDCA and MAFLD. The causality was further confirmed by a double-blind, randomized placebo-controlled trial which showed that n-3 PUFA supplementation significantly increased serum HDCA concentrations in MAFLD subjects in comparison with the control group. The MAFLD mouse model showed that administration of n-3 PUFA mediated hepatic peroxisome proliferator-activated receptor alpha signaling to upregulate oxysterol 7α-hydroxylase (CYP7B1)-centered alternative bile acids synthetic pathway, contributing to increased HDCA concentrations. Administering HDCA to high-fat diet (HFD)-fed mice demonstrated that HDCA acts as an intestinal farnesoid X receptor (FXR) antagonist that decreased intestinal and hepatic ceramide accumulation, thereby ameliorating the MAFLD phenotype. Administration of C16:0-ceramide to HDCA-treated mice reversed the metabolic benefits of HDCA to alleviate hepatic steatosis. Altogether, this work revealed that n-3 PUFA facilitated HDCA synthesis through alternative bile acids synthetic pathway, which mediates the FXR-ceramide axis, providing a novel insight to ameliorate MAFLD.