Mechanisms of Liver Injury by Hepatitis C and Alcohol

丙型肝炎和酒精损伤肝的机制

• 批准号: 8812759
• 负责人: STEVEN A WEINMAN
• 金额: $ 50.11万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-27 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812759
• 关键词: Acetylation; Affect; Affinity; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Antioxidants; Apoptosis; Behavior; Biological Assay; Blood capillaries; Boxing; Cell Cycle Regulation; Cell Nucleus; Cell Proliferation; Cell model; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Complex; Cytosol; DNA Binding; Data; Development; Enzymes; Ethanol; Family; Fibrosis; Foundations; Genetic Transcription; Grant; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocarcinogenesis; Hepatotoxicity; Human; Infection; Injury; Insulin; Isoelectric Focusing; Liver; Liver diseases; Measures; Methods; Mitochondria; Modification; Molecular; Nature; Neoplasms; Nuclear; Nuclear Export; Nuclear Import; Outcome; Oxidative Stress; Patients; Pattern; Phosphorylation; Post-Translational Protein Processing; Primary carcinoma of the liver cells; Process; Research; Resistance; Role; Sampling; Series; Testing; Therapeutic; Transferase; Tumor Suppressor Proteins; Ubiquitin-Conjugating Enzymes; Ubiquitination; Work; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; biological adaptation to stress; capillary; cellular longevity; improved; insulin sensitivity; liver biopsy; liver injury; liver transplantation; loss of function; member; mouse model; nanoscale; novel; oxidant stress; prevent; programs; transcription factor; tumor; upstream kinase

DESCRIPTION (provided by applicant): The combination of Hepatitis C virus (HCV) infection and alcohol consumption produces a more severe liver disease than either condition alone with increased rates of both cirrhosis and hepatocellular carcinoma. We have recently discovered that the combination of HCV and alcohol causes a loss in the activity of the transcription factor FOXO3, a member of the forkhead box family of transcription factors that is responsible for oxidant stress resistance, control of cell proliferation, apoptosis, and insulin sensitivity. FOXO3 is also an established tumor suppressor molecule. Its cellular localization and transcriptional activity are regulated by a series of post translational modifications (PTMs) of the protein. Our preliminary data has shown that either HCV infection alone or alcohol exposure alone increases FOXO3 activity, but the combination of HCV and alcohol results in acetylation of FOXO3 and loss of its transcriptional activity. We also observed decreased FOXO3 activity in liver biopsies from chronic hepatitis C patients and abnormally localized FOXO3 in 85% of HCV-associated hepatocellular carcinomas. The central hypothesis of this proposal is that HCV causes changes in FOXO3 phosphorylation, acetylation and ubiquitination. These PTMs result from altered activity of upstream kinases, acetyl transferases, deacetylases, ubiquitin conjugating enzymes and deubiquitinases. The HCV/alcohol changes in FOXO3 and are responsible for enhanced sensitivity to alcohol and the loss of tumor suppressor activity in hepatocellular carcinoma. Therapeutic approaches targeting FOXO3 have the potential to improve HCV-alcohol associated liver injury and prevent the development of hepatocellular carcinoma. We will examine this hypothesis by three specific aims. They are: (1) to develop a novel nanoscale isoelectic focusing method to determine the nature and mechanism of HCV/ethanol-induced posttranslational modifications of FOXO3; (2) to determine why there is abnormal cytosolic accumulation of FOXO3 in hepatocarcinogenesis and whether this affects tumor behavior; and (3) to examine the role of HCV-induced FOXO3 acetylation in alcohol associated hepatotoxicity and test whether augmenting FOXO3 activity has potential to reduce liver injury. Methods to be employed include a novel isoelectric focusing assay for FOXO3 PTMs, examination of liver explants samples from patients undergoing liver transplantation for hepatocellular carcinoma, and cellular and mouse models of HCV-alcohol interactions. The hypotheses and approaches in this study are highly novel. Successful completion of these studies will identify the molecular changes in FOXO3 that result specifically from the HCV-alcohol interaction, determine how these contribute to cirrhosis and liver carcinogenesis, and use this information to establish the foundation for using FOXO3 manipulation as a therapeutic measure to improve outcome of patients with Hepatitis C and alcohol consumption.

描述（由申请人提供）：丙型肝炎病毒（HCV）感染和饮酒联合产生比单独任何一种情况更严重的肝脏疾病，肝硬化和肝细胞癌的发生率均增加。我们最近发现，HCV和酒精的结合导致转录因子FOXO3活性的丧失，FOXO3是叉头盒转录因子家族的一员，负责抗氧化应激、控制细胞增殖、凋亡和胰岛素敏感性。FOXO3