Docosahexaenoic Acid Modulates Nonalcoholic Fatty Liver Disease by Suppressing Endocannabinoid System.

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. 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. This work elucidates that DHA has improved NAFLD by suppressing endocannabinoid system.

Chen YF ，Fan ZK ，Wang YP ，Liu P ，Guo XF ，Li D ... -  《-》

n-3 polyunsaturated fatty acids in phospholipid or triacylglycerol form attenuate nonalcoholic fatty liver disease via mediating cannabinoid receptor 1/adiponectin/ceramide pathway.

n-3 polyunsaturated fatty acids (PUFA) have shown to exert beneficial effects in the treatment of nonalcoholic fatty liver disease (NAFLD). Supplements of n-3 PUFA occur in either phospholipid or triacylglycerol form. The present study aimed to compare whether the different n-3 PUFA of marine-origin, namely krill oil, DHA/EPA-phospholipid (PL), and EPA/DHA-triacylglycerol (TAG) forms had differential abilities to ameliorate NAFLD. The NAFLD model was established in mice fed a high-fat and high-cholesterol diet (HFD). The mice showed evidence of weight gain, dyslipidemia, insulin resistance and hepatic steatosis after 9 weeks of HFD, while the three forms of the n-3 PUFA reduced hepatic TAG accumulation, fatty liver and improved insulin instance, and hepatic biomarkers after 9 weeks of intervention. Of these, krill oil intervention significantly reduced adipocyte hypertrophy and hepatic steatosis in comparison with DHA/EPA-PL and EPA/DHA-TAG groups. Importantly, only krill oil intervention significantly reduced serum alanine transaminase, aspartate transaminase concentrations and low-density lipoprotein-cholesterol, compared with the HFD group. Supplemental n-3 PUFA lowered circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) concentrations, compared with the HFD group, which was associated with down-regulating CB1 and upregulating adiponectin expressions in adipose tissue. Besides, targeted lipidomic analyses indicated that the increased adiponectin levels were accompanied by reductions in hepatic ceramide levels. The reduced ceramide levels were associated with inhibiting lipid synthesis and increasing fatty acid β-oxidation, finally inhibiting TAG accumulation in the liver. Through mediating CB1/adiponectin/ceramide pathway, the present study suggested that administration of krill oil had superior health effects in the therapy of NAFLD in comparison with DHA/EPA-PL and EPA/DHA-TAG.

Chen YF ，Fan ZK ，Gao X ，Zhou F ，Guo XF ，Sinclair AJ ，Li D ... -  《-》

Dietary DHA/EPA Ratio Changes Fatty Acid Composition and Attenuates Diet-Induced Accumulation of Lipid in the Liver of ApoE(-/-) Mice.

Liu L ，Hu Q ，Wu H ，Wang X ，Gao C ，Chen G ，Yao P ，Gong Z ... -  《-》

Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

Suzuki-Kemuriyama N ，Matsuzaka T ，Kuba M ，Ohno H ，Han SI ，Takeuchi Y ，Isaka M ，Kobayashi K ，Iwasaki H ，Yatoh S ，Suzuki H ，Miyajima K ，Nakae D ，Yahagi N ，Nakagawa Y ，Sone H ，Yamada N ，Shimano H ... -  《PLoS One》

Eicosapentaenoic and docosahexaenoic acid-enriched high fat diet delays the development of fatty liver in mice.

Soni NK ，Nookaew I ，Sandberg AS ，Gabrielsson BG ... -  《Lipids in Health and Disease》