The metabolite 2-Methylbutyrylcarnitine does not Promote Atherosclerosis in Apolipoprotein E-Deficient Mice

Abstract

Background: Although 2-methylbutyrylcarnitine (2MBC) has been associated with metabolic disorders and promotes thrombosis, its effect on atherosclerosis remains elusive. This study was aimed at investigating the role of 2MBC in atherosclerosis development. Methods and Results: Apolipoprotein E-deficient (ApoE −/−) mice were fed a Western diet for 18 weeks to induce atherosclerosis, then administered once-daily gavage with 2MBC or vehicle for 18 weeks. Parameters of systemic lipid metabolism and atherosclerosis were detected. Although 2MBC did not upregulate plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels, the plasma total triglycerides (TG) levels were further upregulated in Western-diet-induced mice treated with 2MBC, thus suggesting that this compound may contribute to hypertriglyceridemia. In addition, 2MBC had no effect on atherosclerosis development, as evidenced by no alterations in plaque area, exacerbation of local inflammation, or effects on plaque stability. RAW264.7 macrophages were used to investigate the effect of 2MBC on oxidized low-density lipoprotein-induced foam cell formation in vitro. Treatment with 2MBC did not affect lipid uptake by foam cells. The addition of 2MBC did not affect the relative mRNA levels of inflammation-associated genes when macrophages were treated with lipopolysaccharide. In addition, to investigate the destructive effects of 2MBC on the vascular endothelium, we stimulated human umbilical vein endothelial cells (HUVECs) with oxidized low-density lipoprotein (ox-LDL). Ox-LDL did not alter the expression levels of monocyte chemotactic protein-1 or vascular cell adhesion molecule-1. Furthermore, 2MBC combined with ox-LDL stimulation did not alter the expression of SR-A1 and ABCA1 in HUVECs. Conclusions: Our study provides the first evidence that 2MBC does not promote atherosclerosis development. This compound does not increase intravascular plaque area, exacerbate the degree of local inflammation, or affect plaque stability in ApoE −/− mice.

Keywords

• 2-methylbutyrylcarnitine
• atherosclerosis
• atherosclerotic plaques