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

Therapeutic approaches with dual lipid-lowering and glucose-lowering properties are clinically advantageous for the treatment of cardiometabolic diseases, including cardiovascular diseases (CVD) and type 2 diabetes (T2D). Current lipid-lowering therapies are known to either increase (statins) or have neutral effects (proprotein convertase subtilisin/kexin type 9 inhibitors) on diabetes risk [1■]. Although the association between cardiometabolic diseases with dyslipidaemia is well recognized, recent metabolomics-based studies have ignited the notion that dysregulated metabolism of specific amino acids may seemingly play a central role in cardiometabolic diseases [2■], Particularly, emerging clinical evidence has identified the lower plasma levels of glycine in patients with insulin resistance or T2D [3,4], acute myocardial infarction (AMI) risk [5■■], acute aortic dissection [6], nonalcoholic fatty liver disease (NAFLD) and obesity [7■], These recent reports highlight a key role for glycine metabolism in cardiometabolic diseases and are supported by mechanistic evidence [8■■,9■,10■,11,12■■,13■,14,15], indicating the role of glycine in metabolic processes engaged in dual glucose and lipid metabolism as well as improving multiorgan metabolic and inflammatory status (e.g. liver and heart, Fig. 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.

Consistent with observational reports of lower plasma glycine levels in patients withT2D [3,4], recent studies indicate that glycine stimulates insulin secretion by acting on glycine receptor (GlyR) in islet β-cells [8■■,9■]. Although glycine beneficial effects on glucose homeostasis have been characterized, its involvement in lipid metabolism and the implication to CVD are only beginning to be elucidated. Recent reports demonstrate that circulating glycine levels are associated with a favourable lipid and inflammatory plasma profile (higher HDL-cholesterol and apolipoprotein A1, lower triglycerides, apolipoprotein B and C-reactive protein), and inversely correlated with AMI risk [5■■,16], Moreover, a recent prospective population-based study demonstrated an association between dietary amino acid pattern of higher glycine load and reduced risk of CVD events [17]. Accordingly, glycine attenuates cardiac hypertrophy and fibrosis in preclinical models by acting on GlyRα2 in cardiomyocytes [10■]. As the underlying cause for most CVD is atherosclerosis, characterized by imbalanced lipid metabolism and inflammation, the above reports indicate a putative antiatherogenic role for glycine.

Glycine, the simplest of all amino acids, serves as substrate for multifaceted metabolic processes, including generation of glutathione, creatine, purines and heme [18], yet how glycine is utilized to exert favourable lipid metabolism is unknown. To address the gap of knowledge regarding the involvement of amino acids in atherosclerosis, we recently analysed the effects of all 20 amino acids on cellular lipid metabolism in macrophages [12■■,19], that play key roles during atherogenesis, with new insights into their proatherogenic crosstalk with adipocytes [20]. Among all amino acids, glycine exerts the most prominent lipid-lowering effects and efficiently inhibits cellular VLDL uptake and triglyceride biosynthesis rates. Glycine deficiency exacerbates Western diet-induced obesity, hypercholesterolaemia, hyperglycaemia and atherosclerosis, whereas glycine treatment yielding supraphysiological steady-state levels is atheroprotective. We are currently pursuing the metabolic and molecular mechanisms underlying the lipid-lowering and antiatherogenic properties of glycine, with indications of regulatory roles in hepatic cholesterol homeostasis.

Another metabolic disorder characterized by imbalanced lipid metabolism and inflammation is NAFLD, a leading cause of chronic liver disease with no currently approved pharmaceutical therapies [21]. Personalized genome-scale metabolic modelling in NAFLD patients, uncovered an inverse association between circulating levels of glycine and its main precursor serine with hepatic steatosis. Moreover, glycine was identified as the limiting substrate for de novo synthesis of the major endogenous antioxidant glutathione, with higher metabolic demand in patients with liver steatosis [13■]. Restored glutathione supply by glycine also protects from diet-induced or ageing-induced vascular dysfunction and inflammation [11]. In accordance with recent reports of lower plasma glycine in NAFLD patients [7■], glycine treatment has recently been shown to protect from NAFLD in preclinical settings. In genetically obese/diabetic KK-A^y mice, dietary glycine supplementation improves both glucose intolerance and hypertriglyceridaemia, preventing body weight gain, hepatic steatosis and inflammation via downregulation of lipogenic genes and improvement of hepatic innate immune microenvironment [14]. Similar effects were reported in Sprague–Dawley rats fed high-fat and sucrose diet, in which glycine supplementation protects from diet-induced liver damage via attenuation of apoptosis, oxidative stress and endoplasmic reticulum stress [15].

Overall, emerging evidence from observational and preclinical studies underscore a relevant role of glycine metabolism in cardiometabolic diseases. Human studies reveal an inverse association between plasma glycine levels and risk of T2D, AMI, NAFLD and obesity. In experimental models, glycine treatment improves glycaemic control, dyslipidaemia, cardiovascular function and steatohepatitis. As depicted in Fig. 1, glycine glucose-lowering and cardioprotective effects are mediated via its actions on GlyRα1 in pancreatic islets and on GlyRα2 in cardiomyocytes, respectively. The role of glycine in improving inflammation may be also explained, at least in part, by serving as a precursor for de novo glutathione synthesis. Dysregulated glycine metabolism is consistently identified as a metabolic biomarker in diabetes, yet additional evidence support inhibition of lipogenic pathways and anti-inflammatory properties, both warrant further investigation. These emerging studies highlight the therapeutic potential of targeting glycine metabolism with relevance to some of the major clinical challenges observed in current cardiometabolic medicine, which include, first, identification of therapies with dual benefits in both glucose and lipid metabolism for the treatment of dyslipidaemia, T2D and CVD. Second, identification of novel therapeutic approaches against NAFLD. A multipronged approach including metabolomics, systems biology, experimental therapeutics, chemical and enzymatic biology is required to further our understating on the therapeutic potential of glycine and establish a glycine-based therapeutic approach. Current efforts are being actively pursued on the following aspects: first, to elucidate glycine antiatherogenic properties and its favourable impact on lipid metabolism and inflammation. Second, to identify chemical and/or enzymatic interactions, glycine mimetics or pharmacological/genetic approaches to leverage endogenous glycine metabolism for enhanced cardiometabolic protection. Third, clinically evaluate glycine abilities to improve glycaemic control and dyslipidaemia and subsequently, to reduce the risk of cardiometabolic diseases. Our studies underscore the integrative role of the simplest amino acid, glycine, as an example of metabolic convergence at the crossroad of lipid and glucose homeostasis.