Defining the role of a novel hexokinase in alcoholic liver disease

定义新型己糖激酶在酒精性肝病中的作用

• 批准号: 10791056
• 负责人: Wei Qiu
• 金额: $ 18.29万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10791056
• 关键词: Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic steatohepatitis; Alcohols; Binding; Biological Assay; Breast Cancer Cell; Cells; Cessation of life; Cirrhosis; Complex; Development; Energy-Generating Resources; Enzymes; Ethanol; Foundations; Glucose; Glycogen; Glycolysis; Grant; Hepatocyte; Hexokinase A; Human; Hypoxia; Impairment; Knockout Mice; Lead; Literature; Liver; Liver Cirrhosis; Metabolic; Mitochondria; Modeling; Molecular; Mus; National Institute on Alcohol Abuse and Alcoholism; Oxidative Phosphorylation; Oxygen; PPAR gamma; Pathogenesis; Patients; Phosphorylation; Phosphotransferases; Play; Process; Production; Rattus; Reaction; Regulation; Research; Role; Sampling; Testing; United States; cell injury; chromatin immunoprecipitation; chronic alcohol ingestion; chronic liver disease; feeding; glucose metabolism; hexokinase; insight; liver injury; liver metabolism; mutant; novel; novel therapeutic intervention; overexpression; promoter; repaired; treatment strategy

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.

抽象的 酒精性肝病（ALD）是全球慢性肝病和肝硬化的主要原因之一 在美国相关死亡。当前对ALD的治疗并不令人满意。新颖的治疗性 迫切需要策略，这需要进一步了解ALD的机制 发展。葡萄糖代谢和糖酵解的失调在ALD发育中起关键作用。作为 葡萄糖磷酸化的关键酶，己糖酶在调节葡萄糖代谢和 糖酵解。最近，含有1（HKDC1）的己糖酶结构域，一种新型的己糖酶，催化了催化剂 葡萄糖的磷酸化并在细胞葡萄糖和肝代谢中起着至关重要的作用，被确定为 酒精性肝炎患者中最上调的激酶。 HKDC1活性增加导致 葡萄糖-6-P和糖原在原发性大鼠肝细胞中的积累。我们最近还发现HDKC1 与正常肝脏相比，人和小鼠酒精脂肪性肝炎（ASH）样品的表达增加。 基于现有文献，我们假设酒精诱导的HKDC1表达促进了糖酵解 和ATP生产，因此是针对酒精引起的肝细胞死亡和ALD的保护机制 发展。这笔赠款的总体目的是回答三个问题：1）有什么影响 HKDC1的过度表达在灰分发育方面有吗？ 2）对于灰分开发是必不可少的HKDC1 发生？ 3）ETOH如何导致HKDC1表达的升高？该提议的结果可能 有可能揭示了ALD发病机理的新型机制，并为发展提供了基础 ALD的新型治疗策略。