Promotion of fatty liver disease by the ASK1 pathway

项目摘要 人类肥胖是一个严重的世界性健康问题，与代谢综合征有关 以及可进展为非酒精性脂肪肝的非酒精性脂肪性肝病(NAFLD) 脂肪性肝炎(NASH)、肝硬变和肝细胞癌(HCC)。非酒精性脂肪肝的估计患病率 约占美国总人口的25%(1)。对NASH流行率的估计令人困惑 由于可靠的非侵入性诊断方法的有限，但大约25%的患者 NAFLD表现为NASH(1)。瘢痕形成(肝硬变)和肝纤维化的发展有助于 肝癌是世界上最常见的肝癌，也是与癌症相关的死亡的第三大原因。 美国(2，3)。 NAFLD/NASH的高发病率是一个主要的健康问题，因为：1)NASH预计会 成为肝移植的主要适应症(4)；和2)NAFLD/NASH相关的肝细胞癌是主要的 美国肥胖相关癌症死亡原因(4)。生活方式干预，包括饮食卡路里 限制和锻炼，是目前治疗的关键方面。然而，还有一种尚未得到满足的有效需求 药物疗法。目前正在开发几种药物，包括减少 脂肪变性，纠正肠道生物失调，促进氧化应激防御，抑制纤维化(5，6)。 最近的研究表明，氧化应激反应蛋白激酶ASK1(属于 MAP3K组)是治疗NASH(5，6)的有前景的药物靶点。小分子Selonsertib是一种 ASK1蛋白激酶活性的有效抑制剂可减少NASH相关的肝纤维化(7，8)，这是一个关键 疾病进展的决定因素(4)。在NASH患者(7，8)中成功的Selonsertib 2期试验有 导致了目前正在进行的第三阶段试验(恒星3和恒星4)(8)。 阻断ASK1有益效果的机制尚不清楚，但可能涉及一种 下游信号通路(如应激激活的MAPK)的激活状态降低。ASK1是 无处不在的表达。因此，目前还没有关于肝细胞类型的信息 介导ASK1促进的NASH的特征，包括肝纤维化。ASK1有可能扮演着一个 在推动肝纤维化的炎症反应中起关键作用(例如在库普弗细胞和其他免疫细胞中) (9)。或者，ASK1可能在促进纤维化的脂肪变性肝细胞中发挥重要作用(10)。它是 也有可能ASK1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ASK1基本功能的相关肝细胞类型尚未得到证实 已定义。此外，在NASH发生过程中调节ASK1的机制不是 明白了。 这项建议旨在确定ASK1信号在NASH发育过程中的机制。 这项研究的完成将为药物的作用机制提供重要的新信息 抑制ASK1的基因。提出了两个具体的目标：1)确定介导肝细胞的类型 ASK1对NASH标志物的影响；2)确定肝脏调节ASK1的机制。 纳什发展公司。 这项研究计划的总体目标是找出导致 ASK1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 预计本研究计划的成功完成将导致确定新的 分子机制。这一知识可能是设计新的治疗策略的基础 针对NASH的治疗，包括合理设计联合疗法。

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.