Effects of n-3 fatty acid treatment on monocyte phenotypes in humans with hypertriglyceridemia

Abstract

Background Hypertriglyceridemia increases risk for atherosclerotic cardiovascular disease and may contribute to atherosclerosis by changing circulating monocyte phenotypes. High-dose n-3 polyunsaturated fatty acids (PUFAs) reduce blood triglyceride levels. Effects of triglyceride-lowering therapy on monocyte phenotypes are not well known. Objective We examined effects of n-3 PUFA treatments (eicosapentaenoic acid [EPA] plus docosapentaenoic acid [DPA] [MAT9001] versus EPA ethyl esters [EPA-EE]) on monocyte phenotypes in individuals with hypertriglyceridemia. Methods Individuals with triglycerides 200–400 mg/dL were recruited. Subjects received two treatments in randomized order for 14 days each: MAT9001 and EPA-EE, at 4 g/day. At 2 days before the start of, and on the last day of, each treatment, nile red staining for lipids and phenotypes of each monocyte subset were examined by flow cytometry after an overnight fast and postprandially after a high-fat meal. Results Treatment with MAT9001 or EPA-EE reduced fasting triglyceride levels and decreased proportions of intermediate monocytes. Only MAT9001 decreased postprandial blood triglyceride levels, lowered fasting nile red levels, indicating less lipid in classical and intermediate monocytes, and reduced postprandial CD11c levels on nonclassical monocytes. MAT9001 and EPA-EE each reduced fasting and postprandial CD11c and CD36 levels on classical and intermediate monocytes and postprandial CCR5 levels on intermediate and nonclassical monocytes, with no significant differences between the two treatments. Conclusions Treatment with MAT9001 in individuals with hypertriglyceridemia reduced fasting nile red staining for lipids in classical and intermediate monocytes. MAT9001 and EPA-EE each improved fasting and postprandial monocyte phenotypes, which could potentially help to protect against atherosclerosis.

Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr−/− Mice

“…Prior to the severe reduction, circulating CD36 + monocytes in Ldlr −/− mice with P407-induced HTG had increased lipid accumulation and elevated levels of CD11c, an adhesion molecule that mediates monocyte adhesion to the endothelium [ 8 , 12 , 45 ]. These changes simulate the phenotypes of monocytes in humans with HTG [ 15 , 16 , 17 , 18 , 19 , 20 ] and consistently support that HTG increases lipid accumulation in monocytes and alters monocyte phenotypes. The increase in monocyte lipid accumulation with P407 injection also suggests that monocytes can acquire circulating lipids independent of LPL, consistent with a previous report [ 46 ].…”

“…Importantly, foamy monocytes occur in humans with familial hypercholesterolemia and may be mechanistically linked to premature ASCVD in these patients [ 13 , 14 ]. Notably, HTG also increases lipid accumulation in monocytes in humans [ 15 , 16 , 17 , 18 , 19 , 20 ]. However, whether foamy monocytes contribute to atherosclerosis in HTG remains to be determined.…”

Leukocyte Activation and Antioxidative Defense Are Interrelated and Moderately Modified by n-3 Polyunsaturated Fatty Acid-Enriched Eggs Consumption—Double-Blind Controlled Randomized Clinical Study

“…This is in line with a study on lipoprotein receptor deficient mice (LDLr−/−) fed a diet rich in fish oil, which exhibited significantly reduced plasma cholesterol levels, frequency of splenic Ly6Chi (classical) monocytes, atherosclerosis, monocyte trafficking into the aortic root, and atherosclerotic lesion macrophage content [ 64 ]. Similar research performed on humans with hypertriglyceridemia showed reduced fasting triglyceride levels and decreased proportions of intermediate monocytes [ 65 ]. Arnardottir HH et al reported that the proportion of classical monocytes in the blood of healthy mice was decreased upon dietary fish oil consumption, but their proportion was increased upon induction of inflammation, thus enhancing microbial defense [ 66 ].…”

Replacing Saturated Fat With Unsaturated Fat in Western Diet Reduces Foamy Monocytes and Atherosclerosis in Male Ldlr –/– Mice

“…Elevated plasma levels of cholesterol and TG transported in lipoproteins play important roles in monocyte uptake of lipids, resulting in formation of FM. 7,8,13,34,46,47 Therefore, decreased plasma levels of TG and cholesterol in mice fed EVOND may lead to less monocyte lipid accumulation and reduced FM formation. Consistently, reduction of hyperlipidemia in humans with familial hypercholesterolemia decreases lipid accumulation within circulating monocytes.…”