High glucose, unsaturated and saturated fatty acids differentially regulate expression of ATP-binding cassette transporters ABCA1 and ABCG1 in human macrophages

Abstract

The ATP-binding cassette transporters ABCA1 and ABCG1 are highly expressed in macrophage-derived foam cells and promote reverse cholesterol efflux via biogenesis of high-density lipoproteins. The aim of this study was to analyze the direct effects of bioactive factors related to the metabolic syndrome on macrophage transcript levels of all 47 human ABC transporters. Using in vitro M-CSF predifferentiated macrophages and TaqMan low density arrays we could show that linoleic acid, palmitic acid, and high glucose levels have a major impact on ABCA1 and ABCG1 expression but do not strongly affect most other human ABC transporters. In Western blot experiments we demonstrate that ABCA1 and ABCG1 protein levels are synchronously suppressed by high glucose levels and the ω6-unsaturated fatty acid linoleic acid. We conclude that metabolites associated with the metabolic syndrome enhance the formation of atherosclerotic lesions by diminishing the reverse cholesterol transport function of ABCA1 and ABCG1.

Diabetes reduces the cholesterol exporter ABCA1 in mouse macrophages and kidneys

“…Thus, diabetes reduces both major macrophage cholesterol exporters but by different mechanisms. It is noteworthy that, of all 49 ABC transporters studied, only expression of ABCA1 and ABCG1 were reduced by high glucose and fatty acids ( 36 ).…”

Insulin Suppresses HDL-Mediated Cholesterol Efflux from Macrophages Through Inhibition of Neutral Cholesteryl Ester Hydrolase and ATP-Binding Cassette Transporter G1 Expressions

“…The direct effect of insulin on ABCG1 expression has been addressed in several studies with inconsistent results 31,32) , although several potential mechanisms have been suggested for insulin signaling [33][34][35] . Previous studies on hyperinsulinemia in human diabetics and in diabetic mice suggested the important role of elevated glucose in the down-regulation of ABCG1 in macrophages 16,36) .…”

Atherogenicity of Monosaccharides, Disaccharides and Artificial Sweeteners in the Lipid-Laden Macrophage Model System: Cell Culture and Mice Studies

“…Accelerated atherosclerosis in diabetic mice was associated with macrophage lipid peroxidation and increased generation of reactive oxygen species (ROS) via induction of NADPH oxidase [7,8]. In addition, macrophages from diabetic mice or under high glucose conditions exhibit lipid accumulation mediated by various mechanisms that regulate intracellular lipid metabolism [7][8][9][10][11][12][13][14][15]. These include enhanced uptake of oxidized (ox)-LDL via up-regulation of the scavenger receptors CD36 and SR-A [7][8][9]11], enhanced cholesterol or triglyceride biosynthesis rates via induction of lipid biosynthesis regulators e.g.…”

“…These include enhanced uptake of oxidized (ox)-LDL via up-regulation of the scavenger receptors CD36 and SR-A [7-9,11], enhanced cholesterol or triglyceride biosynthesis rates via induction of lipid biosynthesis regulators e.g. the sterol regulator elements binding proteins (SREBPs), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or diacylglycerol acyltransferase1 (DGAT1) [12,14], and attenuation of HDL-mediated cholesterol efflux from macrophages via suppression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 [10,13,15].Although the pro-oxidative and pro-atherogenic role of glucose in macrophage foam cell formation has been established, little is Abstract Background: Glucose is known to enhance macrophage foam cell formation and atherosclerosis development. However, the role of other monosaccharides, disaccharides or artificial sweeteners in macrophage atherogenicity remains unclear.…”