Determining the role of glycine in the expression of coagulant and fibrinolytic proteins in the context of obesity

Obesity provokes a chronic low-grade inflammatory state, driving changes in components of the coagulation and fibrinolytic systems that significantly increase the risk of cardiovascular diseases, including heart attacks, stroke, and deep vein thrombosis. However, the precise mechanisms by which obesity promotes a prothrombotic state and subsequent thrombosis development remain unclear. Metabolomic studies from obese subjects revealed an obesity signature highlighted by a decrease in circulating levels of the conditionally essential amino acid glycine, and dietary glycine supplementation has been suggested to reduce obesity-associated metabolic diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we sought to determine the direct effects of glycine on the production of liver-derived coagulation factors. To mimic the inflammatory state and hepatic steatosis observed in obesity, human liver cancer cells (HepG2) were treated with interleukin-6 (IL-6) and palmitate, respectively, and glycine prior to analysis of gene expression and protein levels. Treatment of cells with IL-6 increased the protein and gene expression of fibrinogen (FGA, FGB, FGG), and antiplasmin (SERPINF2), while decreasing expression of tissue plasminogen activator (PLAT) and antithrombin (SERPINC1). Palmitate reduced fibrinogen protein release and increased gene expression of prothrombin (F2) and plasminogen (PLG). With both IL-6 and palmitate, glycine supplementation suppressed fibrinogen gene and protein expression, and F2 and SERPINF2 while increasing expression of PLAT and urokinase plasminogen activator (PLAU). Our results indicate that glycine exposure significantly alters the hepatic coagulation transcriptional program to suppress the obesity-associated prothrombotic state and provides exciting preliminary data to further examine the efficacy of glycine supplementation as a safe and cost-effective approach to alleviate thrombotic disease, particularly in the context of obesity.