The Role of Glycine as a Key Regulator of Hepatic Lipid Metabolism in Non Alcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Despite its increasing prevalence and growing impact on world health, no targeted therapy is yet available. NAFLD encompasses a broad clinical spectrum, ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis and, in severe cases, superimposed hepatocellular carcinoma. Hepatic steatosis is characterized by dysregulated lipid metabolism leading to fat accumulation, mainly triglycerides in the liver and oxidative stress. Recently, the metabolism of several amino acids was found to be altered in NAFLD patients, particularly glycine with decreased blood levels linked to the pathogenesis of the disease. To investigate the role of glycine in regulating lipid metabolism in hepatocytes, we used lipidomic and metabolomic analysis in AMl-12 cells, an immortalized noncancerous hepatocyte cell line, that accumulates lipid droplets. AML-12 cells were incubated with and without glycine and the effect on de novo synthesis of the antioxidant glutathione was measured by tracing 13C labeled glutamine. To investigate the role of glycine in regulating fatty acid oxidation, we measured the ratio of acetylated carnitine to free carnitine (C2/C0 ratio) as well as the flux of 13C labeled palmitate into TCA intermediates. While there was no change in de novo glutathione synthesis, AML-12 cells displayed decrease fatty acid oxidation in the absence of glycine. Glycine can be an important factor in regulating lipid metabolism in hepatocytes and could be used as a treatment strategy for NAFLD.