Fish Oil-Derived Furan Fatty Acid: A New Player in the Regulation of Metabolic Syndrome and Fatty Liver Disease

Abstract Objectives Obesity and non-alcoholic fatty liver diseases (NAFLD) are multifactorial diseases that affect more than 35% of the world's population. Fish oil (FO) is an important dietary component that provides essential omega-3 fatty acids (Ω-3) effective for hypertriglyceridemia with eicosapentaenoic acid shown to reduce cardiovascular and metabolic syndrome-related events. However, the mechanisms involved in these beneficial activities are still unclear. A metabolomic study of healthy volunteers receiving Lovaza, an omega-3-drug, showed a large increase in plasma and urinary metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF). Moreover, in the diet-induced obesity (DIO) mouse model, CMPF was protective and reversed steatosis. We identified furan fatty acids (FuFA) present both in FO and Lovaza (0.1–1%) as the sources of CMPF and hypothesised that they were responsible for these beneficial effects. Methods We synthesized one FuFA and confirmed its structure by NMR and mass spectrometry and tested whether it had protective effects in this DIO model (23 weeks, 60 kcal% fat). After 16 weeks of the diet, FuFA (25mg/kg/day) was administered by gavage for the last 7 weeks. A glucose tolerance test was performed at week 4th. Tissues and blood were collected at week 7th after 5h fasting. Mass spectrometry, ELISA, and multiplex analysis were performed on plasma. Liver staining (H&E) was also performed to quantify steatosis and ballooning. Results The glucose tolerance test showed improved glucose clearance in FuFA-treated mice compared to vehicle. The fasting level of insulin and c-peptide 2 were respectively 2.9- and 1.5-fold lower in FuFA- compared to the vehicle-treated mice. Additionally, circulating TNF-α was significantly lower (1.6-fold) in FuFA-treated mice. NAFLD activity scores - hepatocytes ballooning and steatosis - were also significantly decreased in FuFA-treated mice by 1.6- and 1.4-fold, respectively. Finally, an MS-based analysis of plasma showed a significant decrease in cholesterol (1.2-fold) and cholesterol-ester (1.4-fold) levels in FuFA-treated mice. Conclusions In conclusion, the beneficial effects observed in Ω-3 and FO treatment on DIO and NAFLD may be related to the presence of FuFA in these dietary preparations. Funding Sources NIH.