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Editorial
. 2018 Oct;29(5):428-432.
doi: 10.1097/MOL.0000000000000543.

Emerging therapeutic potential of glycine in cardiometabolic diseases: dual benefits in lipid and glucose metabolism

Oren Rom  1 , Luis Villacorta  1 , Jifeng Zhang  1 , Y Eugene Chen  1 , Michael Aviram  2
Affiliations
Editorial

Emerging therapeutic potential of glycine in cardiometabolic diseases: dual benefits in lipid and glucose metabolism

Oren Rom et al. Curr Opin Lipidol. 2018 Oct.
No abstract available

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Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.
Emerging therapeutic potential of glycine in cardiometabolic diseases. (a) Glycine has been proposed as a biomarker for diabetes onset and progression. Association studies consistently show that plasma glycine levels are low in patients with type 2 diabetes and correlate negatively with insulin resistance. Mechanistically, human islet β-cells express glycine receptor (mainly glycine receptor α1), which mediates a depolarizing Cl− current, enhances action potential firing, Ca2+ entry and insulin secretion from β-cells. In β-cells from donors with type 2 diabetes, glycine receptor α 1 expression and glycine-activated currents are impaired. (b) Plasma glycine levels negatively correlate with acute myocardial infarction risk and are associated with a favourable lipid and inflammatory plasma profile. Mechanistically, glycine acts via glycine receptor α2 to protect against transverse aortic constriction-mediated or angiotensin II-mediated cardiac hypertrophy and fibrosis in mice, by preventing extracellular signal-regulated kinase 1/2 phosphorylation, overexpression of transforming growth factor β, endothelin-1 and collagen I and III. In ageing mice, glycine + N-acetylcysteine (but not N-acetylcysteine alone) reduce leucocyte infiltration and improve cardiac and mitochondrial function. Glycine decreases lipid accumulation in murine macrophages via attenuation of VLDL uptake and triglycerides biosynthesis. (c) Plasma glycine levels are low in patients with nonalcoholic fatty liver disease and obesity and negatively correlate with the severity of hepatic steatosis and obesity. Mechanistic evidence indicates that glycine is the limiting substrate for hepatic biosynthesis of glutathione, which is in higher demand in patients with hepatic steatosis. In genetic and dietary rodent nonalcoholic fatty liver disease models, glycine protects from steatohepatitis via downregulation of lipogenic genes (sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase-1, acetyl-CoA carboxylase, fatty acid synthase), attenuation of lipid peroxidation (reactive oxygen species, 4-hydroxy-2-nonenal), and improvement of hepatic innate immune response (increased M2 transformation of Kupffer cells and natural killer T cells). In 3T3-L1 adipocytes, glycine increases the expression of adiponectin and IL-10. T2D, type 2 diabetes; GlyR, glycine receptor; CVD, cardiovascular diseases; AMI, acute myocardial infarction; HDL-C, HDL cholesterol; apoA1, apolipoprotein A1; TG, triglycerides; apoB, apolipoprotein B; CRP, C-reactive protein; ERK, extracellular signal-regulated kinase; TGF-β, transforming growth factor β; ET-1, endothelin-1; NAFLD, nonalcoholic fatty liver disease; SREBP1c, sterol regulatory element-binding protein-1c; SCD1, stearoyl-CoA desaturase-1; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; ROS, reactive oxygen species; 4-HNE, 4-hydroxy-2-nonenal; NK, natural killer; GSH; glutathione.
See this image and copyright information in PMC

References

REFERENCES AND RECOMMENDED READING

    1. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017; 5:941–950. - PubMed

    2. To date, the FOURIER trial is the largest study (27 564 patients with atherosclerotic disease) of clinical and glycaemic outcomes with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. This study demonstrates that PCSK9 inhibition with evolocumab lowered LDL-cholesterol and significantly reduced cardiovascular risk with greater absolute risk reduction in patients with diabetes. Although previous studies reported that statins increase the risk of new-onset diabetes, in the FOURIER trial, PCSK9 inhibition did not worsen glycaemia over several years and did not increase the risk of new-onset diabetes.

    1. Newgard CB. Metabolomics and metabolic diseases: where do we stand? Cell Metab 2017; 25:43–56. - PMC - PubMed

    2. The review discusses the advances of using metabolomics to identify predictive biomarkers for cardiometabolic diseases and the importance of this approach for understating pathophysiologic mechanisms of such diseases. Emphasis is given to metabolomics-based studies that identified a signature of dysregulated metabolism of specific amino acids such as branched-chain amino acids (BCAAs) and glycine in patients with various forms of cardiometabolic disease.

    1. Floegel A, Stefan N, Yu Z, et al. Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. Diabetes 2013; 62:639–648. - PMC - PubMed
    1. Gar C, Rottenkolber M, Prehn C, et al. Serum and plasma amino acids as markers ofprediabetes, insulin resistance, and incident diabetes. Crit Rev Clin Lab Sci 2018; 55:21–32. - PubMed
    1. Ding Y, Svingen GF, Pedersen ER, et al. Plasma glycine and risk of acute myocardial infarction in patients with suspected stable angina pectoris. J Am Heart Assoc 2016; 5:e002621. - PMC - PubMed

    2. The study of 4109 patients with suspected stable angina pectoris demonstrated, for the first time, that plasma glycine levels are inversely correlated with the risk of acute myocardial infarction (AMI). Significantly, plasma glycine levels are shown to be associated with a favourable lipid profile and lower prevalence of obesity, hypertension, and diabetes mellitus. These findings highlight the importance of elucidating the relationship between glycine metabolism and cholesterol metabolism, particularly in relation to atherosclerosis.

FURTHER RECOMMENDED READING

    1. Cruz M, Maldonado-Bernal C, Mondragón-Gonzalez R, et al. Glycine treatment decreases proinflammatory cytokines and increases interferon-gamma in patients with type 2 diabetes. J Endocrinol Invest 2008; 31:694–699. - PubMed

    2. ■ The study demonstrates that chronic supplementation with glycine (5g/day, 3 months) to 74 patients with T2D significantly reduced the levels of glycated haemoglobin and TNFR1 and increased IFN-γ levels, indicating a role of glycine in glycaemic control and inflammatory response in T2D patients.

    1. Mardinoglu A, Agren R, Kampf C, et al. Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with nonalcoholic fatty liver disease. Nat Commun 2014; 5:3083. - PubMed

    2. ■ The study describes the reconstruction of a genome-scale metabolic model for hepatocytes (iHepatocytes2322) allowing the study of metabolic reprogramming in response to the development of NAFLD. The iHepatocytes2322 model was used to analyse transcriptomics data from NAFLD patients, demonstrating a significant decrease in the expression of genes encoding for enzymes catalysing glycine and serine biosynthesis in patients with nonalcoholic steatohepatitis.

    1. Ruiz-Ramirez A, Ortiz-Balderas E, Cardozo-Saldaña G, et al. Glycine restores glutathione and protects against oxidative stress in vascular tissue from sucrose-fed rats. Clin Sci (Lond) 2014; 126:19–29. - PubMed

    2. ■ The study demonstrates the protective effects of glycine supplementation to sucrose-fed rats on their isolated aortas. Glycine is shown to reduce the release of superoxide anion radical (O2•−) and to decrease lipid peroxidation in relation with increased biosynthesis of glutathione.

    1. Chen J, Ma X, Yang Y, et al. Glycine enhances expression of adiponectin and IL-10 in 3T3-L1 adipocytes without affecting adipogenesis and lipolysis. Amino Acids 2018; 50:629–640. - PubMed

    2. ■ This in-vitro study in 3T3-L1 adipocytes aimed to determine the effects of glycine on adipocyte differentiation, adipogenesis and lipolysis. Although glycine had no significant effects of adipogenesis and lipolysis in the adipocytes, it markedly increased the expression of adiponectin and IL-10, two adipose-derived adipokines with anti-inflammatory properties. These findings provide a possible explanation for the observed antiobesogenic and anti-inflammatory properties of glycine.

    1. Rom O, Aviram M. It is not just lipids: proatherogenic vs. antiatherogenic roles for amino acids in macrophage foam cell formation. Curr Opin Lipidol 2017; 28:85–87. - PubMed

    2. ■ An overview of clinical and mechanistic evidence supporting a role of amino acids in macrophage foam cell formation, atherosclerosis development and cardiovascular diseases risk.

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