Defining the role of a novel hexokinase in alcoholic liver disease

摘要 酒精性肝病(ALD)是全球慢性肝病和肝硬变的主要原因之一。 美国的相关死亡人数。目前ALD的治疗方法并不令人满意。新颖的治疗方法 迫切需要策略，这就需要进一步了解ALD的发病机制 发展。糖代谢和糖酵解的失调在ALD的发生发展中起着关键作用。AS 己糖激酶系葡萄糖磷酸化的关键酶，在调节葡萄糖代谢和糖代谢中起关键作用。 糖酵解。最近，含有1(HKDC1)的己糖激酶域，一种新的催化 葡萄糖的磷酸化在细胞葡萄糖和肝脏代谢中起着至关重要的作用，被认为是 酒精性肝炎患者中最高表达的激酶。HKDC1活动增加有助于 葡萄糖-6-P和糖原在原代大鼠肝细胞中的蓄积。我们最近还发现HDKC1 在人类和小鼠酒精性脂肪性肝炎(ASH)样本中，与正常肝脏相比，其表达增加。 根据现有文献，我们假设酒精诱导的HKDC1表达促进糖酵解 和ATP的产生，从而对酒精诱导的肝细胞死亡和ALD起到保护机制 发展。这笔赠款的总体目标是回答三个问题：1) HKDc1的过度表达对ASH的发展有何影响？2)HKDc1对ASH的发展是否不可或缺 会发生什么？3)乙醇是如何导致HKDC1表达上调的？这项提议的结果可能是 有可能揭示ALD发病的新机制，并为ALD的发展提供基础 ALD的新治疗策略。

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.