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EPA/DHA and Gene Regulation

Why are the longer chain omega-3 fatty acids different from other fatty acids in terms of their biological effects? Likely, the higher number of double bonds starting at carbon 3 from the end gives these fatty acids uniqueness and bioactive properties that were harnessed by organisms over evolutionary time. 

The brain is enriched in long-chain omega-3 fatty acids, particularly DHA found in 20% or more of brain lipids, those found in plasma membranes at the neuronal synapse. 

The basics of omega-3 gene regulation have been provided in summary.  Because of recent reviews and research articles these data are only briefly covered here.  Two main groups of genes are affected by EPA/DHA omega-3s. These groups contain inflammatory genes or energy metabolism genes.

Inflammatory genes are suppressed by EPA/DHA, including cyclooxygenase 2 (COX-2), possibly because of related cox-2 enzyme signaling pathways that use EPA and DHA.  Besides anti-inflammation, pro-endothelial processes are implicated by these data.

Energy-metabolism gene expression is increased by EPA/DHA.  Because lipid metabolism is linked to insulin resistance, treatment of type 2 diabetes by omega-3s is implicated, but likely indirect.  Yet omega-3 dependent reduction in triglyceride levels is thought to be a direct effect, dependent on the lipid biochemical properties of both EPA and DHA with DHA as the longest and most unsaturated fatty acid omega-3.

Because lipid metabolism is linked to insulin resistance, treatment of type 2 diabetes by omega-3s is implicated, but likely indirect. Notably, in treated hypertensive type 2 diabetic patients either EPA or omega-3 DHA independently reduced oxidative stress and EPA and omega-3 DHA reduced triglyceride levels in these patients.  DHA may also act as free and as acyl-CoA conjugated fatty acids, implicating Long-chain Acyl-CoA Synthetases (ACSLs) in their activation. Because ACSLs are regulated by peroxisome proliferator-activated receptors (PPAR), by analyzing specific ACSL isoforms via RT-PCR, ACSL expression patterns in tissues could provide some insight into omega-3 metabolism. Also, metabolized forms of EPA and DHA bind to the PPAR family of transcription factors, which may differentially regulate ACSL isoforms in different tissues. Therefore, bioactive PPAR ligands derived from DHA potentially signal through ACSLs to activate genes in a positive feedback loop that could make the effects of DHA increasingly effectual as tissues regulators of lipid homeostasis.Genes influencing innate and acquired immunity in type 1 diabetes is also an area of active research. How omega-3s affect these would be interesting to know.

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