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Adenosine Kinase: Nutritional Regulation and Role in Diet-Induced NAFLD
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Adenosine is at the crossroad of transmethylation reactions and adenosine signaling. Therefore, by regulating adenosine concentration, adenosine kinase (ADK) has been identified as an upstream regulator of a complex metabolic network. However, ADK-based therapeutics has been largely limited to neural diseases, and the relationship between ADK dysfunction and non-alcoholic fatty liver disease (NAFLD) has never been investigated to date. Since the liver is the major site for methylation reactions, and ADK widely expresses throughout the body with the highest abundance in the liver, we hypothesize that hepatic ADK dysfunction might be a novel contributor to diet-induced NAFLD. By employing liver-specific ADK knockout and overexpression mouse models, in the present study, we first confirmed the upregulation of hepatic ADK in response to High-fat diet (HFD) feeding. We then proved a protective role of hepatic ADK knockout in aspects of HFD-induced NAFLD, including insulin resistance, excessive fat deposition, and low-grade metabolic inflammation in the liver. Additionally, we observed that hepatic ADK overexpression predisposed mice to NAFLD without an HFD challenge. Lastly, we touched on the mechanisms of action and determined that following upregulated ADK expression upon HFD feeding, the global DNA hypermethylation and subsequent silencing of genes of target, peroxisome proliferator-activated receptor α (PPARα) in specific, could be the primary mechanism underlying ADK action. Besides, the reduced adenosine signaling mediated by adenosine 2A receptor (A₂AR) took a limited effect in exacerbating the aforementioned pathological process. Taken together, our research indicated the causal effects of hepatic ADK overexpression on diet-induced NAFLD. Even though more studies are warranted to further extend the mechanisms, ADK-oriented strategies hold huge promise in terms of effectively treating NAFLD.
Zhou, Jing (2019). Adenosine Kinase: Nutritional Regulation and Role in Diet-Induced NAFLD. Doctoral dissertation, Texas A&M University. Available electronically from