Defining the role of a novel hexokinase in alcoholic liver disease

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Abstract Alcoholic liver disease (ALD) is one of the primary causes of chronic liver disease worldwide and cirrhosis- associated deaths in the United States. Current treatments for ALD are not satisfactory. Novel therapeutic strategies are desperately needed, which warrants a further understanding of the mechanisms of ALD development. Dysregulation of glucose metabolism and glycolysis plays a critical role in ALD development. As key enzymes of phosphorylation of glucose, hexokinases play critical roles in regulating glucose metabolism and glycolysis. Recently, the hexokinase domain containing 1 (HKDC1), a novel hexokinase that catalyzes the phosphorylation of glucose and plays a vital role in cellular glucose and liver metabolism, was identified as the most up-regulated kinase in patients with alcoholic hepatitis. Increased HKDC1 activity contributed to the accumulation of glucose-6-P and glycogen in primary rat hepatocytes. We recently also found that HDKC1 expression is increased in human and mouse alcoholic steatohepatitis (ASH) samples compared to normal livers. Based on the existing literature, we hypothesize that alcohol-induced HKDC1 expression promotes glycolysis and ATP production, thus serving as a protective mechanism against alcohol-induced hepatocyte death and ALD development. The Overall Objective of this grant is to answer three questions: 1) What impact does the excessive expression of HKDC1 have on ASH development? 2) Is HKDC1 indispensable for ASH development to occur? 3) How does EtOH lead to an elevation in HKDC1 expression? The results of this proposal could potentially reveal novel mechanisms for ALD pathogenesis and provide the groundwork for the development of novel treatment strategies for ALD.