Modulation of Macrophage Fatty Acid Content and Composition by Exposure to Dyslipidemic Serum in Vitro

Abstract

Macrophages in arterial walls accumulate lipids leading to the development of atherosclerotic plaques. However, mechanisms underlying macrophage lipid accumulation and foam cell formation are often studied without accounting for risk factors such as dyslipidemia. We investigated the effect of varying concentrations of triglyceride (TG) within physiological range on macrophage fatty acid (FA) accumulation and expression of cholesterol efflux proteins. Human monocytes were cultured in media supplemented with 10% sera containing low (0.7 mmol/L) to high (1.4 mmol/L) TG. The resulting macrophages were harvested after 10 days for analysis of FA content and composition and expression of genes involved in lipid metabolism. Exposure to higher TG and lower HDL concentrations in media increased macrophage lipid content. Macrophages exposed to higher TG had increased total FA content compared with controls (876 μg/mg protein vs. 652 μg/mg protein) and greater proportions of C16:0, C18:1 and C18:2. Macrophage expression of both ABCA1 and ABCG1 cholesterol efflux proteins were reduced when higher TG concentrations were present in the media. Expression of scavenger receptor CD36, involved in lipoprotein uptake, was also downregulated in macrophages exposed to higher TG. Culturing macrophages in conditions of higher versus lower TG influenced macrophage FA content and composition, and levels of regulatory proteins. Replicating in vitro levels of dyslipidemia encountered in vivo may provide an informative model for investigation of atherogenesis.

DNA Methylation of Lipid-Related Genes Affects Blood Lipid Levels

“…The author suggests that hypertriglyceridemia may increase the risk of CAD via direct actions on macrophages favoring foam cell formation, thus leading to the development of atherosclerotic plaque. 44 Changes in ABCG1 DNA methylation might mediate the development of atherosclerotic plaques in response to high triglyceride levels. Thus, with this study, we found hints for a new perspective on the molecular background of CAD.…”

Stearic Acid Accumulation in Macrophages Induces Toll-Like Receptor 4/2-Independent Inflammation Leading to Endoplasmic Reticulum Stress–Mediated Apoptosis

“…1, 2 Additionally, recent studies indicate that macrophages of atherosclerotic plaques accumulate FFAs; 13–15 however, the molecular consequences of intracellular FFAs remain relatively unknown. Increased partitioning of FFA to TG (via DGAT-1 overexpression) protects macrophages from FFA-induced inflammation, 31 suggesting that accumulation of FFAs, rather than TG, in these immune cells may be responsible for inflammatory signaling.…”

“…13 In addition, treatment of human macrophages with dyslipidemic serum increases intracellular FFA concentrations. 14, 15 Therefore, determining the consequences of intracellular FFA accumulation within macrophages is of critical importance. Our lab has previously shown that accumulation of the saturated FFA, stearic acid, in macrophages results in apoptotic cell death; 16 however, the mechanism of lipotoxicity remains unknown.…”

“…In addition, recent data indicate that macrophages in atherosclerotic plaques accumulate FFAs; 13–15 however, the molecular consequences of FFA accumulation in these immune cells remain ill defined. We have previously demonstrated that triacsin C (TC)-mediated inhibition of long-chain acyl-CoA synthetases (ACSL) during stearic acid treatment of mouse peritoneal macrophages (MPMs) increases intracellular stearic acid concentrations and results in apoptotic cell death.…”

Parametric Determination of Hypoxic Ischemia in Evolution of Atherogenesis

“…Macrophages in particular implicate a series of converging events that sequentially re-define in repetitive form the dynamics of atherogenesis. Dyslipidemmia increases lipid content in foam cells found in atherosclerotic plaques (Wong et al, 2011).…”