Role of Histone Deacetylase 4 in Alcoholic Liver Disease

组蛋白脱乙酰酶 4 在酒精性肝病中的作用

基本信息

批准号：
10491272
负责人：
Ji-Young Lee
金额：
$ 19.12万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10491272
关键词：
Alcohol abuse Alcoholic Hepatitis Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcohols Animals Area Attenuated Biochemical Biological Assay Candidate Disease Gene Cause of Death Cells Chronic Cirrhosis Data Development Disease Ethanol Future Gastrointestinal Diseases Gene Expression Gene Expression Alteration Gene Silencing Genes Genetic Transcription Goals HDAC4 gene Health Heavy Drinking Hepatic Hepatocyte Histologic Histone Deacetylase Histones Human Inflammation Inflammatory Interleukins Investigation Knock-out Knockout Mice Liver Mediating Mediator of activation protein Messenger RNA Molecular Molecular Profiling Morbidity - disease rate Mus Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Patients Play Primary carcinoma of the liver cells Process Protein Isoforms Proteins Public Health Reactive Oxygen Species Regulation Regulator Genes Repression Role SIRT1 gene Specimen Testing Therapeutic Tissues alcohol exposure alcohol prevention base cell injury feeding genome-wide hepatocellular carcinoma cell line holistic approach in vivo in vivo Model inhibitor innovation interest knock-down liver injury macrophage molecular marker mortality mouse model novel overexpression therapeutically effective transcriptome transcriptome sequencing transcriptomics translational potential

项目摘要

PROJECT SUMMARY Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. ALD is the eighth most common cause of mortality in the U.S. and the second leading cause of death among all gastrointestinal diseases. Alcoholic hepatitis (AH) is the progressive form of ALD, which can progress to cirrhosis and hepatocellular carcinoma. Therefore, there is an unmet need for developing effective therapeutic strategies for AH. Evidence suggests histone deacetylases (HDACs) are involved in alcohol-induced cell damages. However, little is known about the role of each HDAC isoform in the pathogenesis of AH. We found that HDAC4 mRNA and protein levels were markedly increased in the human liver with alcoholic cirrhosis and the mouse liver exposed to alcohol. Furthermore, our preliminary data indicate that ethanol increased HDAC4 expression in Huh-7 cells, a human hepatocellular carcinoma cell line. Also, ethanol induced the expression of Hdac4 with concomitant increases in inflammation and oxidative stress in macrophages, which was significantly attenuated when Hdac4 was knocked out or down. Sirtuin 1 (SIRT1) is known to prevent alcohol-related cell damages and liver injury. Consistently, we found that a SIRT1 inhibitor increased interleukin-1b (Il1b) expression, whereas a SIRT1 activator significantly abolished ethanol-induced Hdac4 and Il1b expression in macrophages. It is of interest that Hdac4 deficiency increased Sirt1 expression, while human HDAC4 overexpression elicited the opposite effects in RAW 264.7 macrophages. The preliminary results suggest the HDAC4/SIRT1 axis may play a crucial role in the development of AH. Based on the strong premise described above, we establish the central hypothesis that the deletion of Hdac4 in hepatocytes or macrophages inhibits the development of AH by altering hepatic expression of genes, including SIRT1, that are critically involved in alcohol-induced inflammation and oxidative stress. We will take both targeted (SIRT1 pathway) and untargeted approaches (genome-wide transcriptome analysis) using novel mice that have hepatocyte- or macrophage-specific deletion of Hdac4 under chronic-binge ethanol feeding (the NIAAA model) as in vivo models. We will test the hypothesis by pursuing the following two Specific Aims: 1) to determine the role of hepatocyte and macrophage HDAC4 in the development of AH and to evaluate the HDAC4/SIRT1 axis for the pathogenesis of AH; and 2) to conduct a genome-wide transcriptome analysis to identify HDAC4-regulated genes in hepatocytes and macrophages that mediate the pathogenic processes of AH and to corroborate the findings using human liver specimens and primary human hepatocytes and macrophages. The findings from this exploratory study will produce much-needed information on the role of hepatocyte and macrophage HDAC4 in the pathogenesis of AH. Also, this study will lead to the discovery of new genes/pathways, which can be exploited for future therapies for AH. Therefore, a significant impact on public health is anticipated upon completion of this study.

项目概要酒精性肝病（ALD）是全世界发病和死亡的主要原因。 ALD 排名第八是美国常见的死亡原因，也是所有胃肠道疾病死亡的第二大原因疾病。酒精性肝炎 (AH) 是 ALD 的进展形式，可进展为肝硬化和肝细胞癌。因此，开发有效的治疗策略的需求尚未得到满足啊。有证据表明组蛋白脱乙酰酶 (HDAC) 参与酒精诱导的细胞损伤。然而，关于每种 HDAC 亚型在 AH 发病机制中的作用知之甚少。我们发现HDAC4 mRNA 酒精性肝硬化的人类肝脏和小鼠肝脏中的蛋白质水平显着增加肝脏接触酒精。此外，我们的初步数据表明乙醇增加了 HDAC4 在Huh-7细胞（一种人肝细胞癌细胞系）中表达。此外，乙醇诱导表达 Hdac4 的减少伴随着巨噬细胞炎症和氧化应激的增加，这是当 Hdac4 被敲除或下调时，该作用显着减弱。 Sirtuin 1 (SIRT1) 已知可预防酒精相关的细胞损伤和肝损伤。一致地，我们发现 SIRT1 抑制剂增加了白细胞介素 1b (Il1b) 表达，而 SIRT1 激活剂显着消除乙醇诱导的 Hdac4 和 Il1b 在巨噬细胞中的表达。有趣的是，Hdac4 缺乏会增加 Sirt1 表达，而人类 HDAC4 过度表达在 RAW 264.7 中引起相反的效果巨噬细胞。初步结果表明 HDAC4/SIRT1 轴可能在 AH的发展。基于上述强有力的前提，我们建立中心假设：肝细胞或巨噬细胞中 Hdac4 的缺失可通过改变肝脏功能来抑制 AH 的发展包括 SIRT1 在内的基因表达，这些基因与酒精引起的炎症和氧化反应密切相关压力。我们将采取靶向（SIRT1 途径）和非靶向方法（全基因组转录组）分析）使用在慢性暴食下具有肝细胞或巨噬细胞特异性 Hdac4 缺失的新型小鼠乙醇喂养（NIAAA 模型）作为体内模型。我们将通过以下两个方面来检验这个假设具体目标： 1) 确定肝细胞和巨噬细胞 HDAC4 在 AH 和评估 HDAC4/SIRT1 轴对 AH 发病机制的影响； 2) 进行全基因组转录组分析分析以确定肝细胞和巨噬细胞中介导致病性的 HDAC4 调节基因 AH 的过程并使用人类肝脏标本和原代人类肝细胞证实这些发现和巨噬细胞。这项探索性研究的结果将产生急需的有关作用的信息肝细胞和巨噬细胞 HDAC4 在 AH 发病机制中的作用。此外，这项研究将导致新的发现基因/途径，可用于未来的 AH 治疗。因此，对公众影响很大完成本研究后预计健康状况良好。