Promotion of fatty liver disease by the ASK1 pathway

项目摘要 人类肥胖是一个严重的全球性健康问题，与代谢综合征有关 以及非酒精性脂肪性肝病（NAFLD）的发展， 脂肪性肝炎（NASH）、肝硬化和肝细胞癌（HCC）。NAFLD的估计患病率 在美国，大约占人口的25%（1）。NASH患病率的估计值存在混淆 可靠的非侵入性诊断方法有限，但大约25%的患者 NAFLD表现为NASH（1）。瘢痕形成（肝硬化）和肝纤维化的发展有助于 HCC是最常见的肝癌，也是癌症相关死亡的第三大原因， USA（2，3）. NAFLD/NASH的高发病率代表了一个主要的健康问题，因为：1）预计NASH 成为肝移植的主要适应症（4）; 2）NAFLD/NASH相关HCC是肝移植的主要适应症。 美国肥胖相关癌症死亡原因（4）。生活方式干预，包括饮食热量 限制和锻炼是当前治疗的关键方面。然而，对于有效的 药物治疗.目前正在开发几种药物，包括减少 脂肪变性、纠正肠道生态失调、促进氧化应激防御和抑制纤维化（5，6）。 最近的研究已经确定，氧化应激反应蛋白激酶ASK 1（一个成员， MAP 3 K组）是治疗NASH的有前景的药物靶标（5，6）。小分子Selonsertib是一种 一种有效的ASK 1蛋白激酶活性抑制剂，可减少NASH相关肝纤维化（7，8），这是一个关键 疾病进展的决定因素（4）。Selonsertib在NASH患者中的成功II期试验（7，8） 导致目前正在进行的3期试验（STELLAR 3和STELLAR 4）。 阻断ASK 1的有益作用的机制尚不清楚，但可能涉及一种新的机制。 下游信号传导途径（例如应激激活的MAPK）的激活状态降低。ASK 1是 无处不在的表达。因此，没有关于肝细胞类型的信息， 介导ASK 1促进的NASH标志，包括肝纤维化。有可能ASK 1扮演了一个 在驱动肝纤维化的炎症反应（如枯否细胞和其他免疫细胞）中的关键作用 （九）、或者，ASK 1可能在促进纤维化的脂肪变性肝细胞中发挥重要作用（10）。是 也可能ASK 1的关键作用可能是直接参与肝纤维化的星状细胞（11）。 因此，在NASH中介导ASK 1基本功能的相关肝细胞类型尚未被证实。 定义了此外，在NASH发展过程中介导ASK 1调节的机制并不重要。 明白 该提案旨在确定NASH发展过程中ASK 1信号传导的机制。 这项研究的完成将提供有关药物作用机制的重要新信息 抑制ASK 1。提出了两个具体的目的：1）确定介导肝细胞类型， ASK 1对NASH标志物的影响;以及2）确定在NASH期间调节ASK 1的肝脏机制。 NASH发展。 这项研究计划的总体目标是确定分子机制，占 ASK 1在NASH中的作用这一目标的实现将增加对NASH发展的理解。我们 预计这项研究计划的成功完成将导致新的识别 分子机制这些知识可能是设计新的治疗策略的基础 治疗NASH，包括联合治疗的合理设计。

Project Summary Human obesity represents a serious world-wide health problem that is associated with metabolic syndrome and the development of non-alcoholic fatty liver disease (NAFLD) that can progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). The estimated prevalence of NAFLD in the USA is approximately 25% of the population (1). Estimates for the prevalence of NASH are confounded by the limited availability of reliable non-invasive methods for diagnosis, but approximately 25% of patients with NAFLD exhibit NASH (1). The development of scarring (cirrhosis) and hepatic fibrosis contributes to the development of HCC, the most common liver cancer and the 3rd leading cause of cancer-related death in the USA (2, 3). The high incidence of NAFLD/NASH represents a major health problem because: 1) NASH is anticipated to become the leading indication for liver transplantation (4); and 2) NAFLD/NASH-associated HCC is the primary cause of obesity-related cancer death in the USA (4). Lifestyle interventions, including dietary calorie restriction and exercise, are key aspects of current therapy. However, there is an unmet need for effective pharmacotherapy. Several medications are currently under development, including approaches to reduce steatosis, correct intestinal dysbiosis, promote oxidative stress defense, and suppress fibrosis (5, 6). Recent studies have established that the oxidative stress-responsive protein kinase ASK1 (a member of the MAP3K group) is a promising drug target for the treatment of NASH (5, 6). The small molecule Selonsertib is a potent inhibitor of ASK1 protein kinase activity that causes reduced NASH-related hepatic fibrosis (7, 8), a key determinant of disease progression (4). Successful phase 2 trials of Selonsertib in NASH patients (7, 8) have led to phase 3 trials (STELLAR 3 and STELLAR 4) that are currently in progress (8). The mechanism that accounts for the beneficial effects of blocking ASK1 is unknown, but likely involves a reduction in the activation state of down-stream signaling pathways (e.g. stress-activated MAPK). ASK1 is expressed ubiquitously. Consequently, no information is available concerning the hepatic cell type that mediates the ASK1-promoted hallmarks of NASH, including hepatic fibrosis. It is possible that ASK1 plays a key role in an inflammatory response (e.g. in Kupffer cells and other immune cells) that drives hepatic fibrosis (9). Alternatively, ASK1 may play an important role in steatotic hepatocytes that promotes fibrosis (10). It is also possible that the key role of ASK1 may be in stellate cells that are directly involved in hepatic fibrosis (11). The relevant hepatic cell type that mediates the essential function of ASK1 in NASH has therefore not been defined. Moreover, the mechanism that mediates ASK1 regulation during the development of NASH is not understood. This proposal is designed to identify the mechanism of ASK1 signaling during NASH development. Completion of this study will provide important new information concerning the mechanism of action of drugs that inhibit ASK1. Two Specific Aims are proposed: 1) To identify the hepatic cell type that mediates the effects of ASK1 on hallmarks of NASH; and 2) To identify hepatic mechanisms that regulate ASK1 during NASH development. The overall goal of this research program is to identify molecular mechanisms that account for the function of ASK1 in NASH. Achievement of this goal will increase understanding of NASH development. We anticipate that the successful completion of this research program will lead to the identification of new molecular mechanisms. This knowledge may represent a basis for the design of novel therapeutic strategies for the treatment of NASH, including the rational design of combination therapies.