Dihomo-γ-linolenic acid inhibits several key cellular processes associated with atherosclerosis

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1865; no. 9; pp. 2538 - 2550
• Main Authors: Gallagher, Hayley, Williams, Jessica O., Ferekidis, Nele, Ismail, Alaa, Chan, Yee-Hung, Michael, Daryn R., Guschina, Irina A., Tyrrell, Victoria J., O'Donnell, Valerie B., Harwood, John L., Khozin-Goldberg, Inna, Boussiba, Sammy, Ramji, Dipak P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2019; Elsevier
• Subjects: 8,11,14-Eicosatrienoic Acid - pharmacology; Animals; Atherosclerosis; Atherosclerosis - metabolism; Atherosclerosis - pathology; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Cytokines - metabolism; Dihomo-γ-linolenic acid; Foam cells; Foam Cells - cytology; Foam Cells - metabolism; Gene expression; Gene Expression Regulation - drug effects; Humans; Inflammation; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Interleukin-1beta - pharmacology; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Knockout; Mitochondria - drug effects; Mitochondria - metabolism; Monocytes - cytology; Smooth muscle cells; Apo; ABC; MCP-1; HASMC; Dihomo-γ-linolenic acid; LXR; FCCP; ICAM-1; Macrophages; LY; LPS; AcLDL; TBHP; IFN-γ; NEFA; Atherosclerosis; oxLDL; STAT-1; HUVEC; RT-qPCR; Foam cells; SR; CE; IL; PUFA; PGE1; DGLA; Inflammation; Smooth muscle cells; Gene expression; PBMC; ECM; HMDM; CVD; VCAM-1; TNF-α; LA; PDGF; VSMC; FC; GLA
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2019.06.011

Atherosclerosis and its complications are responsible for one in three global deaths. Nutraceuticals show promise in the prevention and treatment of atherosclerosis but require an indepth understanding of the mechanisms underlying their actions. A previous study showed that the omega-6 fatty acid, dihomo-γ-linolenic acid (DGLA), attenuated atherosclerosis in the apolipoprotein E deficient mouse model system. However, the mechanisms underlying such protective effects of DGLA are poorly understood and were therefore investigated. We show that DGLA attenuates chemokine-driven monocytic migration together with foam cell formation and the expression of key pro-atherogenic genes induced by three pro-inflammatory cytokines in human macrophages. The effect of DGLA on interferon-γ signaling was mediated via inhibition of signal transducer and activator of transcription-1 phosphorylation on serine 727. In relation to anti-foam cell action, DGLA inhibits modified LDL uptake by both macropinocytosis and receptor-mediated endocytosis, the latter by reduction in expression of two key scavenger receptors (SR-A and CD36), and stimulates cholesterol efflux from foam cells. DGLA also improves macrophage mitochondrial bioenergetic profile by decreasing proton leak. Gamma-linolenic acid and prostaglandin E1, upstream precursor and key metabolite respectively of DGLA, also acted in an anti-atherogenic manner. The actions of DGLA extended to other key atherosclerosis-associated cell types with attenuation of endothelial cell proliferation and migration of smooth muscle cells in response to platelet-derived growth factor. This study provides novel insights into the molecular mechanisms underlying the anti-atherogenic actions of DGLA and supports further assessments on its protective effects on plaque regression in vivo and in human trials. •Dihomo-γ-linolenic acid (DGLA) attenuates atherosclerosis in a mouse model system.•The mechanisms underlying anti-atherogenic actions of DGLA are poorly understood.•DGLA inhibited atherogenic processes in three key cell types in this disease.•Mechanisms underlying such protective actions of DGLA were identified.•Studies inform on the beneficial anti-atherogenic actions of DGLA.