Pathways affected by n-3 PUFA

n-3 polyunsaturated fatty acids (n-3 PUFA) modulate multiple molecular pathways that together contribute to their physiological effects. First, the physicochemical properties of cellular and organelle membranes are influenced by their lipid composition (center). Incorporation of n-3 PUFA into these membranes alters membrane fluidity and biophysics of lipid rafts that modulate protein function and signaling events. For example, enrichment of cellular membranes with n-3 PUFA disrupts dimerization and recruitment of toll-like receptor-4, which might contribute to anti-inflammatory effects by down-regulation of nuclear factor-kappaB (NF-kB) activation. Ion channels such as sodium (Na⁺), L-type calcium (Ca²⁺), and Na⁺– Ca²⁺ exchangers might be similarly modulated by n-3 PUFA incorporation into lipid membranes. Second, n-3 PUFA seem to directly interact with membrane channels and proteins (center). For example, direct modulation of ion channels or G-protein-coupled receptor 120 (GPR 120) might contribute to antiarrhythmic or antiinflammatory effects, respectively. Third, n-3 PUFA directly regulate gene expression via nuclear receptors and transcription factors (lower right). n-3 PUFA are natural ligands of many key nuclear receptors in multiple tissues, including peroxisome proliferator-activated receptors (PPAR; -alpha, -beta, -delta, and -gamma), hepatic nuclear factors (HNF-4; -alpha and -gamma), retinoid X receptors (RXR), and liver X receptors (alpha and beta). Interactions between n-3 PUFA and nuclear receptors are modulated by cytoplasmic lipid binding proteins (eg, fatty acid [FA] binding proteins) that transport the FAs into the nucleus. n-3 PUFA also alter function of transcription factors such as sterol regulatory element binding protein-1c (SREBP-1c). Such genetic regulation contributes to observed effects of n-3 PUFA on lipid metabolism and inflammatory pathways. Fourth, after release from phospholipids by cytosolic phospholipase A₂ (cPLA₂), PUFA including n-3 PUFA are converted to eicosanoids by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes (lower left). n-3 PUFA displace arachidonic acid (AA) in membrane phospholipids, reducing the production of AA-derived eicosanoids (eg, prostaglandin E₂ [PGE₂]) while increasing those generated from n-3 PUFA. This altered eicosanoid profile might influence inflammation, thrombosis, and vascular function. Fifth, emerging evidence suggests that n-3 PUFA play an important role in inflammation resolution via specialized pro-resolving mediators (SPMs), including resolvins or protectins that are n-3 PUFA metabolites derived from actions of COX and LOX (top). Biosynthesis of SPMs seems to require involvement of two or more cell types ("transcellular biosynthesis"), with one cell type converting the n-3 fatty acid to metabolic intermediates, and the second cell type converting these intermediates into the SPMs. n-3 PUFA-derived SPMs seem to be key drivers of inflammation resolution programs that reduce chronic inflammation in a wide range of animal models. The roles of each of these molecular pathways in the cardiovascular protection of n-3 PUFA represent promising areas for future investigation.