Specific Amino Acids Affect Cardiovascular Diseases and Atherogenesis via Protection against Macrophage Foam Cell Formation: Review Article

Abstract

The strong relationship between cardiovascular diseases (CVD), atherosclerosis, and endogenous or exogenous lipids has been recognized for decades, underestimating the contribution of other dietary components, such as amino acids, to the initiation of the underlying inflammatory disease. Recently, specific amino acids have been associated with incident cardiovascular disorders, suggesting their significant role in the pathogenesis of CVD. Special attention has been paid to the group of branched-chain amino acids (BCAA), leucine, isoleucine, and valine, since their plasma values are frequently found in high concentrations in individuals with CVD risk. Nevertheless, dietary BCAA, leucine in particular, have been associated with improved indicators of atherosclerosis. Therefore, their potential role in the process of atherogenesis and concomitant CVD development remains unclear. Macrophages play pivotal roles in the development of atherosclerosis. They can accumulate high amounts of circulating lipids, through a process known as macrophage foam cell formation, and initiate the atherogenesis process. We have recently screened for anti- or pro-atherogenic amino acids in the macrophage model system. Our study showed that glycine, cysteine, alanine, leucine, glutamate, and glutamine significantly affected macrophage atherogenicity mainly through modulation of the cellular triglyceride metabolism. The anti-atherogenic properties of glycine and leucine, and the pro-atherogenic effects of glutamine, were also confirmed in vivo. Further investigation is warranted to define the role of these amino acids in atherosclerosis and CVD, which may serve as a basis for the development of anti-atherogenic nutritional and therapeutic approaches.

Conflict of interest statement

Conflict of interest: No potential conflict of interest relevant to this article was reported.

Figures

Figure 1. Amino Acids Affect Macrophage Foam Cell Formation through Regulation of Lipid Metabolism

Leucine and glycine significantly prevented triglyceride accumulation in macrophages, by inhibiting triglyceride-rich very-low-density lipoprotein (VLDL) uptake and triglyceride biosynthesis rate, while glutamine showed the opposite effects, accompanied by a concurrent upregulation of diacylglycerol acyltransferase-1 (DGAT1). Leucine also decreased macrophage cholesterol content by inhibiting the rate of cholesterol biosynthesis and increasing serum-mediated cholesterol efflux from macrophages, whereas glutamine increased the uptake of cholesterol-rich low-density lipoproteins (LDL), with concomitant accumulation of cholesterol mass. Macrophage mitochondrial respiration and ATP production were improved after leucine supplementation. Red-colored up-arrows (indicating increase or upregulation) and compounds names, designate pro-atherogenic effects; green-colored up-arrows, crossed circles (indicating decrease or inhibition), and compounds names, designate anti-atherogenic effects. ABCA1, ABCG1, ATP-binding cassette subfamily A or G member 1; DGAT1, diacylglycerol acyltransferase-1; FA, fatty acids; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LDLR, LDL receptor; SR-B1, scavenger receptor type B-1; TG, triglycerides; VLDL, very-LDL.

Figure 2. Oxidative Status and Lipid Metabolism upon Addition of Glycine- or Leucine-Rich Proteins (Fibroin or Casein, Respectively) to Cultured J774A.1 Macrophages

Quantifications were performed after cell incubation with fibroin (glycine-rich), casein (leucine-rich), or only glycine, followed by: (A) Intracellular ROS generation measured by 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA); (B) Cholesterol mass; (C) Triglyceride mass; (D) VLDL uptake, using fluorescein isothiocyanate (FITC)-labeled VLDL; (E) Triglyceride biosynthesis rate after cell incubation with [3H]-oleic acid; (F) Triglyceride degradation rate versus Control.