In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice

Abstract

and GPR120/FFAR4 that are activated by short-, medium-, or long-chain FAs (1-6). GPR120/FFAR4 is highly expressed in intestine, adrenals, lung, adipose tissue, and macrophages, and is described as the n-3 PUFA receptor (7). Upon activation by n-3 PUFA, GPR120/FFAR4 inhibits transforming growth factor -activated kinase 1 activation, resulting in attenuation of IKKB/NF-B and JNK/AP1 signaling (7). GPR120/FFAR4 expression regulates obesity in mice and humans; a nonsynonymous mutation (p.R270H) inhibited GPR120/FFAR4 signaling activity, resulting in increased risk of obesity in European populations (8). In vivo, selective activation of GPR120/FFAR4 by n-3 PUFAs is anti-inflammatory and insulin sensitizing (7,8). High-fat diet-fed GPR120/FFAR4 KO mice versus WT counterparts supplemented with n-3 PUFA or a selective GPR120/ FFAR4 agonist (cpdA) (9) have: 1) increased adipose tissue F4/80+ macrophage infiltration and pro-inflammatory/ M1 gene expression, 2) increased M1 gene expression in lipopolysaccharide-stimulated peritoneal macrophages, and 3) increased insulin resistance. Collectively, these findings highlight the anti-inflammatory potential of macrophage GPR120/FFAR4 activation by n-3 PUFA. However, the impact of GPR120/FFAR4 expression on atherosclerosis progression, particularly in the context of dietary FA composition, is unknown.Abstract G protein-coupled receptor (GPR)120/FFA receptor (FFAR)4 (GPR120/FFAR4) activation by n-3 PUFAs attenuates inflammation, but its impact on atherosclerosis is unknown. We determined whether in vivo activation of leukocyte GPR120/FFAR4 by n-3 versus n-6 PUFAs is atheroprotective. Leukocyte GPR120/FFAR4 WT or KO mice in the LDL receptor KO background were generated by bone marrow transplantation. Mice were fed one of the four atherogenic diets containing 0.2% cholesterol and 10% calories as palm oil (PO) + 10% calories as: 1) PO, 2) fish oil (FO; 20:5 n-3 and 22:6 n-3 enriched), 3) echium oil (EO; 18:4 n-3 enriched), or 4) borage oil (BO; 18:3 n-6 enriched) for 16 weeks. Compared with PO, mice fed BO, EO, and FO had significantly reduced plasma cholesterol, TG, VLDL cholesterol, hepatic neutral lipid, and atherosclerosis that were equivalent for WT and KO mice. In BO-, EO-, and FO-fed mice, but not PO-fed mice, lack of leukocyte GPR120/ FFAR4 resulted in neutrophilia, pro-inflammatory Ly6C hi monocytosis, increased aortic root monocyte recruitment, and increased hepatic inflammatory gene expression. In conclusion, leukocyte GPR120 expression has minimal effects on dietary PUFA-induced plasma lipid/lipoprotein reduction and atheroprotection, and there is no distinction between n-3 versus n-6 PUFAs in activating anti-inflammatory effects of leukocyte GPR120/FFAR4 in vivo.

Role of Borage Seed Oil and Fish Oil with or without Turmeric and Alpha- Tocopherol in Prevention of Cardiovascular Disease and Fatty Liver in Rats

“…Fish oil and borage oil were reported previously to reduce T.Ch, T.Gs and hepatic lipids in mice 44 which agreed with the current research. Oleic acid a monounsaturated fatty acid which is present as 20.163 and 12.771 in borage and fish oil, respectively were reported to have cardioprotective effect via improving vascular endothelial function 45 .…”

Dietary PUFAs attenuate NLRP3 inflammasome activation via enhancing macrophage autophagy

“…We have demonstrated that botanical oils enriched in 18-carbon FAs beyond D6D [echium oil (EO), containing 18:4 n-3, and borage oil (BO), containing 18:3 n-6] result in efficient conversion and enrichment of their respective ≥20-carbon PUFAs, 20:5 n-3 and 20:4 n-6. Furthermore, compared with the saturated/monounsaturated FA-enriched palm oil (PO), dietary enrichment with EO or BO reduced plasma cholesterol concentrations, splenic monocytosis, neutrophilia, monocyte trafficking into aortic plaques, and atherosclerosis, similar to results observed with FO consumption ( 22 – 24 ).…”

“…At 8 weeks of age, mice were randomly assigned to one of four groups consuming atherogenic diets containing 10% calories as PO and 0.2% cholesterol, supplemented with an additional 10% of calories as 1 ) PO, 2 ) BO (18:3 n-6 enriched), 3 ) EO (18:4 n-3 enriched), or 4 ) FO (20:5 n-3 and 22:6 n-3 enriched) for an additional 8–16 weeks. We also performed bone marrow transplantation as previously described ( 24 ). Briefly, bone marrow cells were harvested from cleaned femurs and tibias of male WT and atg5 MSKO mice and injected into irradiated (900 rads) Ldlr −/− mice (stock 002207) (7 × 10 6 bone marrow cells per mouse).…”

Oral administration of the selective GPR120/FFA4 agonist compound A is not effective in alleviating tissue inflammation in mouse models of prototypical autoimmune diseases

“…Notably, the in vivo significance of GPR120/FFA4 to suppress chronic low‐grade inflammation also has lately been contended. While GPR120/FFA4 activation by ω3‐PUFAs was initially reported to be critical to reduce high‐fat diet‐induced adipose tissue inflammation, more recent studies found GPR120/FFA4 to be dispensable for the therapeutic effects of ω3‐PUFAs in mouse models of both high‐fat diet‐induced adipose tissue inflammation, and of atherosclerosis . The reason for these discrepant findings is unknown and numerous explanations are conceivable.…”

“…While GPR120/FFA4 activation by ω3-PUFAs was initially reported to be critical to reduce high-fat diet-induced adipose tissue inflammation, 14 more recent studies found GPR120/FFA4 to be dispensable for the therapeutic effects of ω3-PUFAs in mouse models of both high-fat diet-induced adipose tissue inflammation, and of atherosclerosis. 35,36 The reason for these discrepant findings is unknown and numerous explanations are conceivable. Inflammation is a most complex process and ω3-PUFAs can exert diverse pharmacological actions independent of GPR120/FFA4.…”