Role of the ubiquitin E3 ligase HUWE1 in age-associated nonalcoholic fatty liver disease

泛素 E3 连接酶 HUWE1 在年龄相关性非酒精性脂肪肝中的作用

• 批准号: 10648621
• 负责人: Manabu Kurokawa
• 金额: $ 20.4万
• 依托单位: KENT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648621
• 关键词: ADD-1 protein; Affect; Age; Aging; Animal Model; Body Weight; Body Weight decreased; CD36 Antigens; Characteristics; Cholesterol; Chronic; Cirrhosis; Clinical; Coupled; Data; Deposition; Development; Diet; Disease; Etiology; Exercise; FDA approved; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Goals; Heavy Drinking; Hepatic; Hepatocyte; Homeostasis; Individual; Inflammation; Knock-out; Knockout Mice; Label; Lipids; Liver; Liver diseases; MCL1 gene; Measures; Mediating; Mediator; Medical; Metabolic; Molecular; Mus; Normal tissue morphology; Ohio; Outcome; Pathogenesis; Pathology; Pathway interactions; Physiological; Play; Population; Primary carcinoma of the liver cells; Proteins; Proteomics; Quality Control; Regulation; Research; Resistance; Risk; Risk Factors; Role; Signal Pathway; Signaling Molecule; Specialist; TP53 gene; Tamoxifen; Techniques; Testing; Therapeutic; Time; Triglycerides; Ubiquitination; Universities; data modeling; diet and exercise; hepatocyte injury; high risk; human disease; in vivo; inhibitor; knockout gene; lifestyle intervention; lipid biosynthesis; lipid metabolism; liver injury; mouse model; non-alcoholic fatty liver; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; prevent; protein degradation; therapeutic target; transcription factor; transcriptome sequencing; ubiquitin-protein ligase; uptake

Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide and is estimated to affect nearly 30% of the population. Rather than a single disorder, NAFLD refers to a spectrum of conditions that are characterized by excessive fat accumulation in the liver (hepatic steatosis) that occurs independently of excessive alcohol ingestion. With increased hepatocyte injury and inflammation, hepatic steatosis can progress to nonalcoholic steatohepatitis (NASH), followed by cirrhosis and fibrosis which lead to increased risk for developing hepatocellular carcinoma (HCC). Although hepatic steatosis can be reversed in early NAFLD with weight loss, diet, and exercise, liver damage resulting from inflammation, cirrhosis, and fibrosis observed in advanced NAFLD is often deemed irreversible. Therefore, there is a critical need to identify molecular mechanisms contributing to NALFD etiology and progression to identify therapeutic targets before the disease becomes clinically unmanageable. While several factors are known to contribute to the onset and progression of NAFLD-related disorders, aging is one of the highest risk factors. However, the mechanism underlying age- associated NAFLD remain incompletely understood. HUWE1 is a HECT-domain ubiquitin E3 ligase ubiquitously expressed in normal tissues. HUWE1 ubiquitinates a wide range of cellular substrates, including p53, MYC, and MCL1. Given the diverse substrates, the in vivo role of HUWE1 in human disease remains elusive. We have recently identified that HUWE1 is a critical mediator of NAFLD etiology as liver-specific Huwe1 knockout rendered mice protected against hepatic steatosis induced by age. Our novel data suggest that dysregulation of hepatic HUWE1 may play an important role in the pathogenesis of age-associated NAFLD. To test this hypothesis, we will identify the mechanism of how HUWE1 promotes age-associated NAFLD (Aim 1) and identify the substrate of HUWE1 that prevents the disease in mice (Aim 2). The successful completion of the proposed study will establish HUWE1 as a key regulator of age-associated NAFLD. This outcome will have a durable impact in the field since it will uncover a signaling pathway previously unrecognized and provide a rationale for investigating the mechanism of HUWE1 regulation in aging hepatocytes.

摘要 非酒精性脂肪性肝病（NAFLD）是世界范围内最常见的肝脏病理学， 近30%的人口。NAFLD不是一种单一的疾病，而是指一系列的疾病， 特征在于肝脏中的过度脂肪积聚（肝脂肪变性），其独立于 过量饮酒随着肝细胞损伤和炎症的增加，肝脂肪变性可以进展 非酒精性脂肪性肝炎（NASH），其次是肝硬化和纤维化，导致风险增加， 发展为肝细胞癌（HCC）。虽然肝脏脂肪变性可以在早期NAFLD中逆转， 体重减轻，饮食和运动，炎症引起的肝损伤，肝硬化和纤维化，观察到的 晚期NAFLD通常被认为是不可逆的。因此，迫切需要鉴定分子 有助于NALFD病因和进展的机制，以在疾病发生前确定治疗靶点 临床上无法控制虽然已知有几个因素有助于发病和进展 在NAFLD相关疾病中，衰老是最高风险因素之一。然而，年龄背后的机制- 相关的NAFLD仍然不完全了解。HUWE 1是一种HECT结构域泛素E3连接酶， 在正常组织中表达。HUWE 1泛素化广泛的细胞底物，包括p53，MYC， MCL1.鉴于底物的多样性，HUWE 1在人类疾病中的体内作用仍然难以捉摸。我们有 最近发现HUWE 1是NAFLD病因学的关键介质，因为肝脏特异性Huwe 1敲除 使小鼠免受年龄诱导的肝脂肪变性。我们的新数据表明， 肝脏HUWE 1可能在年龄相关性NAFLD的发病机制中发挥重要作用。为了验证这一 假设，我们将确定HUWE 1如何促进年龄相关的NAFLD（目的1）的机制，并确定 HUWE 1的底物，可预防小鼠的疾病（目的2）。成功完成拟议的 这项研究将确立HUWE 1作为年龄相关NAFLD的关键调节因子。这一结果将具有持久的 它将揭示一个以前未被认识到的信号通路，并提供一个基本原理， 研究HUWE 1在衰老肝细胞中的调节机制。