Arachidonic acid as a target for treating hypertriglyceridemia reproduced by a causal network analysis and an intervention study

Fatty acids, as a heterogeneous source of energy within all cell types, are stored as triacylglycerol in highly regulated lipid droplets, which when released by lipolysis is the primary source of long-chain fatty acids utilized in the body. There are two essential fatty acids: linoleic acid (omega-6) and alpha-linolenic acid (omega-3), which have been recognized as necessary dietary components for normal health (Spector and Kim 2015). Cardiovascular research have provided evidence of the salutary effects of omega-3 carboxylic acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Both are considered to reduce triglyceride levels and non-high-density lipoprotein cholesterol levels in patients with severe hypertriglyceridemia (Leaf 2008). In contrast, omega-6 fatty acids, particularly arachidonic acid (AA), are precursors of inflammatory eicosanoids, which contribute to a cardiovascular disease phenotype (Capra et al. 2013). To examine the relationship between individual fatty acids and total lipoprotein lipids, we reviewed data from two independent analyses. The Atherosclerosis Risk in Communities (ARIC) Study is a population study (The ARIC Investigators 1989). This study provided the data for our integration of genomic, metabolomics, and triglyceride levels using a systems approach called genome directed acyclic graph (G-DAG), to identify pathways among fatty acids and their influence on triglycerides in an observational study (Yazdani et al. 2016a, b, c, d). The Epanova study (Maki et al. 2014) examined the effect of supplementation with pharmaceutical omega-3 fatty acids and circulating lipoprotein lipid levels in the EVOLVE trial. This study was a reanalysis of the “Epanova for Lowering Very high triglycerides” (EVOLVE) trial (Kastelein et al. 2014). Interestingly, both the analysis of the ARIC study (Yazdani et al. 2016a, b, c, d) and that of the EVOLVE study (Kastelein et al. 2014) indicate that changes in levels of AA are the best corresponding indicator of triglycerides.

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