Hepatocyte apoptosis links to decreased TET1 and 5-hydroxymethylcytosine formation: Possible role of α-Ketoglutarate in alcoholic and non-alcoholic fatty liver diseases

Background and Aim: α-Ketoglutarate (α-KG) is an intermetabolite in the TCA cycle, and reportedly contributes to a decrease in reactive oxygen species and an increase in lifespan. An α-KG dependent methylcytosine dioxygenase, TET1 modifies 5-methylcytosine (5-mC), an epigenetic mark on the DNA into 5-hydroxymethylcytosine (5hmc), leading to DNA demethylation and transcriptional activation. Little information is available about the relation between modulation of 5hmC formation and alcoholic liver disease (ALD) progression. Method: A rat ALD model was used to study 5hmC in relationship to hepatocyte apoptosis. Human ALD liver samples were also used to validate these findings. Results: Chronic ethanol feeding significantly reduced 5hmC formation in a rat ALD model. TET1 expression was substantially reduced in the ethanol-fed rats and was accompanied by both an increased in hepatocyte apoptosis and an elevated expression of the DNA damage marker. Mechanistic studies revealed targeting TET1 activity by removing co-substrate promoted apoptosis and DNA damage. Related to the results, we also found its coenzyme α-KG antagonized the drug-induced DNA damage. Additionally, dietary α-KG inhibit hepatic steatosis progression in  high-fat diet-fed mice. Conclusion: TET1-mediated 5hmC is involved in hepatocyte apoptosis in ALD. The co-substrate of TET1, α-KG may potentially be a therapy for the lifestyle-related liver diseases.