Glyoxal-derived advanced glycation end-products, N^ε-carboxymethyl-lysine, and glyoxal-derived lysine dimer induce apoptosis-related gene expression in hepatocytes

Background: Advanced glycation end-products (AGEs) are proteins or lipids that have been glycated nonenzymatically by reducing sugars and their derivatives such as methylglyoxal. AGEs are known to cause inflammation, oxidative stress, and diseases in the human body. The toxic effects of AGEs and their structures on the origin of the protein being modified have not been well studied. Methods and results: Five different types of AGEs: AGE1 (glucose-derived), AGE2 (glyceraldehyde-derived), AGE3 (glycolaldehyde-derived), AGE4 (methylglyoxal-derived), and AGE5 (glyoxal-derived); were used to examine the effect of AGEs on HepG2 cells. AGE2 through 5 increase the production of reactive oxygen species (ROS) in liver cells, an initiating factor for apoptosis. At the mRNA and protein levels, AGE5 treatment showed the greatest increase in expression of apoptosis-related factors such as Bax, p53, and Caspase 3. Quantitative analysis revealed that N^ε-carboxymethyl-lysine (CML) and glyoxal-lysine dimer (GOLD) were the important types of AGE5. The ROS generation and the expression of apoptotic factors both increased when cells were treated with CML and GOLD. Conclusion: These findings suggest that AGE5 treatment activates the apoptosis-related gene expression in hapatocytes, with CML and GOLD as potential major AGE compounds.