Docosahexaenoic Acid Modulates Nonalcoholic Fatty Liver Disease by Suppressing Endocannabinoid System

Scope Endocannabinoid signaling regulates energy homeostasis, and is tightly associated with nonalcoholic fatty liver disease (NAFLD). The study previously finds that supplementation of docosahexaenoic acid (DHA) has superior function to ameliorate NAFLD compared with eicosapentaenoic acid (EPA), however, the underlying mechanism remains elusive. The present study aims to investigate whether DHA intervention alleviates NAFLD via endocannabinoid system. Methods and results In a case–control study, the serum endocannabinoid ligands in 60 NAFLD and 60 healthy subjects are measured. Meanwhile, NAFLD model is established in mice fed a high‐fat and ‐cholesterol diet (HFD) for 9 weeks. DHA or EPA is administrated for additional 9 weeks. Serum primary endocannabinoid ligands, namely anandamide (AEA) and 2‐arachidoniylglycerol (2‐AG), are significantly higher in individuals with NAFLD compared with healthy controls. NAFLD model shows that serum 2‐AG concentrations and adipocyte cannabinoid receptor 1 expression levels are significantly lower in DHA group compared with HFD group. Lipidomic and targeted ceramide analyses further confirm that endocannabinoid signaling inhibition has exerted deletion of hepatic C16:0‐ceramide contents, resulting in down‐regulation of de novo fatty acid synthesis and up‐regulation of fatty acid β‐oxidation related protein expression levels. Conclusions This work elucidates that DHA has improved NAFLD by suppressing endocannabinoid system. The case–control study demonstrates that NAFLD subjects have shown higher cannabinoid ligand levels, suggesting that activating endocannabinoid system might be associated with initiation and progression of NAFLD. Animal study reveals a novel mechanism that DHA supplementation could effectively inhibit endocannabinoid system accompanied with depleted hepatic C16:0‐ceramide contents, resulting in inhibition of hepatic TAG accumulation.