GLYCINE/SARCOSINE RATIO AS NOVEL BIOMARKER FOR ALCOHOL-INDUCED LIVER FIBROSIS UNDER SUMOYLATION CONTROL

Abstract

Alcohol-induced liver fibrosis/disease (ALD) is characterized by excessive deposition of extracellularmatrix (ECM) components in response to chronic abuse that could lead to cirrhosis and hepatocellularcarcinoma development. Sarcosine is a derivative of the amino acid glycine, formed by the enzymesglycine N-methyl transferase (GNMT) or dimethylglycine dehydrogenase (DMGDH) and convertedback into glycine via sarcosine dehydrogenase (SARDH). GNMT is silenced in human alcohol-inducedcirrhosis. In addition, GNMT knockout mice develop oxidative stress, liver injury, fibrosis, and HCC.SUMOylation is a post-translational modification that requires an essential E2-conjugating enzyme 9(UBC9) to covalently bind of small ubiquitin modifier (SUMO) and plays an important role in a widerange of cellular processes. We previously demonstrated that UBC9 level is induced in intragastricethanol-infusion (EI) treated mouse liver. We performed SUMO-proteomics of alcohol-fed mouse liverand identified altered sumoylation of GNMT and SARDH. The goal of this work is to examine whetherthe dysregulated SUMOylation could regulate GNMT and SARDH enzymatic function in ethanolinducedliver fibrosis and elucidate the molecular mechanism(s).