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

摘要 非酒精性脂肪性肝病(NAFLD)是全世界最常见的肝脏病理，据估计影响 近30%的人口。NAFLD指的不是单一的疾病，而是一系列的疾病 以肝脏中脂肪过度堆积(肝脏脂肪变性)为特征，这种脂肪堆积独立于 过量饮酒。随着肝细胞损伤和炎症的增加，肝脏脂肪变性可能会恶化。 到非酒精性脂肪性肝炎(NASH)，然后是肝硬变和纤维化，这会增加患上 发展中的肝细胞癌。尽管肝脏脂肪变性可以在早期NAFLD中被逆转 体重减轻、饮食和运动、炎症、肝硬变和纤维化导致的肝损伤 晚期非酒精性脂肪肝通常被认为是不可逆转的。因此，迫切需要鉴定分子 NALFD的病因和进展机制有助于在疾病前确定治疗靶点 在临床上变得无法控制。虽然已知有几个因素导致了该病的发生和发展 在NAFLD相关疾病中，年龄是最高风险因素之一。然而，年龄背后的机制-- 相关的非酒精性脂肪肝仍未完全了解。HUWE1是一种普遍存在的Hect结构域泛素E3连接酶 在正常组织中表达。HUWE1泛素化多种细胞底物，包括P53、MYC和 MCL1.鉴于底物的多样性，HUWE1在人类疾病中的体内作用仍然难以捉摸。我们有 最近发现HUWE1是肝脏特异性HUWE1基因敲除的NAFLD病因学的关键介质 使小鼠免受年龄引起的肝脏脂肪变性的影响。我们的新数据表明， 肝脏HUWE1可能在年龄相关性NAFLD的发病机制中起重要作用。为了测试这一点 假设，我们将确定HUWE1如何促进年龄相关NAFLD的机制(目标1)并确定 在小鼠中预防疾病的HUWE1的底物(目标2)。圆满完成拟议中的 研究将确定HUWE1是年龄相关的NAFLD的关键调节因子。这一结果将产生持久的 在现场的影响，因为它将发现以前未被识别的信号通路，并为 探讨HUWE1对衰老肝细胞的调节机制。

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.