Omega-3 carboxylic acids and fenofibrate differentially alter plasma lipid mediators in patients with non-alcoholic fatty liver disease

Fibrates and omega-3 polyunsaturated acids (n-3PUFA) are used for the treatment of hypertriglyceridemia but have not demonstrated consistent effects on cardiovascular (CV) risk. In this study we investigate how these two pharmacological agents influence plasma levels of bioactive lipid mediators, aiming to explore their efficacy beyond that of lipid-lowering agents. Plasma from overweight patients with non-alcoholic fatty liver disease and hypertriglyceridemia, participating in a randomized placebo-controlled study investigating the effects of 12 weeks treatment with fenofibrate or omega-3 free carboxylic acids (OM-3CA) (200 mg or 4g per day, respectively), were analysed for eicosanoids and related PUFA species, N-acylethanolamines and ceramides. OM-3CA reduced plasma concentrations of proinflammatory PGE2, as well as PGE1, PGD1 and TXB2 but increased prostacyclin, and EPA- and DHA-derived lipids of LOX and CYP (e.g. 17-HDHA, 18-HEPE, 19,20-DiHDPA). Fenofibrate reduced plasma concentrations of vasoactive CYP-derived eicosanoids (DHETs). Although OM-3CA increased plasma levels of the N-acylethanolamines DHEA and DPEA, and fenofibrate increased POEA, the effect of both treatments may have been masked by the placebo (olive oil). Fenofibrate was more efficacious than OM-3CA in significantly reducing plasma ceramides, pro-inflammatory lipids associated with CV disease risk. Neither treatment affected putative lipid species associated with NAFLD. Our results show that OM-3CA and fenofibrate differentially modulate the plasma mediator lipidome, with OM-3CA promoting the formation of lipid mediators with potential effects on chronic inflammation, while fenofibrate mainly reducing ceramides. These findings suggest that both treatments could ameliorate chronic inflammation with possible impact on disease outcomes, independent of triglyceride reduction.