The Role of α-Linolenic Acid and Its Oxylipins in Human Cardiovascular Diseases

Abstract

α-linolenic acid (ALA) is an essential C-18 n-3 polyunsaturated fatty acid (PUFA), which can be elongated to longer n-3 PUFAs, such as eicosapentaenoic acid (EPA). These long-chain n-3 PUFAs have anti-inflammatory and pro-resolution effects either directly or through their oxylipin metabolites. However, there is evidence that the conversion of ALA to the long-chain PUFAs is limited. On the other hand, there is evidence in humans that supplementation of ALA in the diet is associated with an improved lipid profile, a reduction in the inflammatory biomarker C-reactive protein (CRP) and a reduction in cardiovascular diseases (CVDs) and all-cause mortality. Studies investigating the cellular mechanism for these beneficial effects showed that ALA is metabolized to oxylipins through the Lipoxygenase (LOX), the Cyclooxygenase (COX) and the Cytochrome P450 (CYP450) pathways, leading to hydroperoxy-, epoxy-, mono- and dihydroxylated oxylipins. In several mouse and cell models, it has been shown that ALA and some of its oxylipins, including 9- and 13-hydroxy-octadecatrienoic acids (9-HOTrE and 13-HOTrE), have immunomodulating effects. Taken together, the current literature suggests a beneficial role for diets rich in ALA in human CVDs, however, it is not always clear whether the described effects are attributable to ALA, its oxylipins or other substances present in the supplemented diets.

Keywords: DiHOTrE; EpODE; HOTrE; cardiovascular disease; inflammation; lipid mediators; mortality; oxo-OTrE; oxylipins; α-linolenic acid.

Figure 1

Schematic illustration of the oxylipins derived from ALA after enzymatic metabolism. 9S-hydroperoxyoctadecatrienoic acid (9S-HpOTrE) and 13S-hydroperoxyoctadecatrienoic acid (13S-HpOTrE) are produced from ALA via the 15-lipoxygenase (15-LOX) pathway, and are further hydrolyzed to 9S- and 13S-hydroxyoctadecatrienoic acid (9S-HOTrE and 13S-HOTrE), respectively. 9S-HOTrE is further oxidized to 9-oxo-octadecatrienoic acid (9-oxo-OTrE) and further hydroxylated to 9,16-dihydroxyoctadecatrienoic acid (9,16-DiHOTrE), respectively, the 4 stereoisomers of which have also been studied. 12-9Z,13E/Z,15Z-hydroxyoctadecatrienoic acid (12-9Z,13E/Z,15Z—HOTrE) is produced as the major metabolic product of ALA via the cyclooxygenase (COX) pathway, mainly by enzymatic action of the COX-2 enzyme. Cytochrome P450 (CYP) epoxygenase activity through the CYP2 isoforms CYP4502C2 and CYP4502CAA results in the formation of 9,10-, 12,13- and 15,16-epoxyoctadecadienoic acids (9,10-EpODE, 12,13-EpODE and 15,16-EpODE), which are further hydrolyzed to their corresponding dihydroxyoctadecadienoic acids (9,10-DiHODE, 12,13-DiHODE, 15,16-DiHODE) through the soluble epoxide hydrolase enzyme. The CYP450 isoform CYP2U1 metabolizes ALA to produce 18-hydroxyoctadecatrienoic acid (18-HOTrE).

Figure 2

Schematic summary of the known mechanisms through which n3-PUFA ALA and its oxylipins influence the inflammatory response. α-linolenic acid (ALA) from diet or supplements incorporates at SN₂ in cell membrane phospholipids and can be released by phospholipase A₂ (PLA₂) upon a cellular signal. ALA can then activate peroxisome proliferator-activated receptor gamma (PPAR-γ) or can be metabolized into oxylipins, which, in turn, can themselves act as ligands for PPAR-γ. PPAR-γ heterodimerizes with the retinoid X receptor (RXR) and this signaling pathway is known to regulate processes of lipid metabolism and inflammation. Created with BioRender.com (accessed on 9 February 2023).