Palmitate promotes monocyte atherogenicity via de novo ceramide synthesis.
Elevated plasma free fatty acids (FAs) are associated with increased risk of cardiovascular disease. This study investigates the effects of the saturated FA palmitate and unsaturated FA oleate on monocyte phenotype and function. Incubation of human U937 and THP-1 monocytes with palmitate for 24h increased cell surface expression of integrin CD11b and scavenger receptor CD36 in a concentration-dependent manner with some decrease in mitochondrial reducing capacity at high concentration (300 μM). Monocytes incubated with palmitate, but not oleate, showed increased uptake of oxidized LDL and increased adhesion to rat aortic endothelium, particularly at bifurcations. The palmitate-induced increase in CD11b and CD36 expression was associated with increased cellular C16 ceramide and sphingomyelin, loss of reduced glutathione, and increased reactive oxygen species (ROS). Increased monocyte surface CD11b and CD36 was inhibited by fumonisin B1, an inhibitor of de novo ceramide synthesis, but not by the superoxide dismutase mimetic MnTBap. In contrast, MnTBap prevented the mitochondrial ROS increase and metabolic inhibition due to 300μM palmitate. This study demonstrates that in viable monocytes, palmitate but not oleate increases expression of surface CD11b and CD36. Palmitate increases monocyte adhesion to the aortic wall and promotes uptake of oxidized LDL and this involves de novo ceramide synthesis.
School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
Dan
D
Gao
Chathyan
C
Pararasa
Christopher R
CR
Dunston
Clifford J
CJ
Bailey
Helen R
HR
Griffiths
D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D049109:Cell Proliferation; D002518:Ceramides / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019301:Oleic Acid / Q000494:pharmacology; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000494:pharmacology*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D039481:CD11b Antigen; D018955:CD36 Antigens; D002518:Ceramides; C509295:ITGAM protein, human; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D019301:Oleic Acid; D019308:Palmitic Acid; D005978:Glutathione