The Role of Glyoxalase-I (Glo-I), Advanced Glycation Endproducts (AGEs), and Their Receptor (RAGE) in Chronic Liver Disease and Hepatocellular Carcinoma (HCC)

Glyoxalase-I (Glo-I) and glyoxalase-II (Glo-II) comprise the glyoxalase system and are responsible for the detoxification of methylglyoxal (MGO). MGO is formed non-enzymatically as a by-product, mainly in glycolysis, and leads to the formation of advanced glycation endproducts (AGEs). AGEs bind to their receptor, RAGE, and activate intracellular transcription factors, resulting in the production of pro-inflammatory cytokines, oxidative stress, and inflammation. This review will focus on the implication of the Glo-I/AGE/RAGE system in liver injury and hepatocellular carcinoma (HCC). AGEs and RAGE are upregulated in liver fibrosis, and the silencing of RAGE reduced collagen deposition and the tumor growth of HCC. Nevertheless, data relating to Glo-I in fibrosis and cirrhosis are preliminary. Glo-I expression was found to be reduced in early and advanced cirrhosis with a subsequent increase of MGO-levels. On the other hand, pharmacological modulation of Glo-I resulted in the reduced activation of hepatic stellate cells and therefore reduced fibrosis in the CCl(4)-model of cirrhosis. Thus, current research highlighted the Glo-I/AGE/RAGE system as an interesting therapeutic target in chronic liver diseases. These findings need further elucidation in preclinical and clinical studies.