A novel pathway controls liver injury in NASH

项目摘要 非酒精性脂肪性肝病(NAFLD)已成为一种普遍的健康风险。非酒精性脂肪性肝炎 (NASH)，以肝脏脂肪变性、炎症、肝损伤和纤维化为特征，可导致 肝硬化和肝癌，这两种疾病都需要肝移植。尽管NASH是可逆的，但没有 已获FDA批准的治疗药物。这种毁灭性疾病的发病机制仍然很不清楚。 明白了。因此，研究NASH发病的分子机制并鉴定 潜在的治疗靶点具有重要意义。肝细胞死亡引起的肝损伤是最主要的 NASH的特征，典型的特征是肝活检中出现气球状的肝细胞 考试。在正常肝脏中，肝细胞凋亡在肝脏内稳态、维持平衡方面起着关键作用。 肝细胞丢失和替换之间的关系。然而，病理条件包括酒精或非酒精 脂肪性肝炎会导致广泛的肝细胞死亡和肝损伤。大量研究表明，肝细胞 死亡是触发NAFLD进展、发展为肝硬变和肝癌的关键事件。 因此，了解控制肝细胞死亡的分子机制可能会导致新的 纳什的治疗。代谢应激，如营养过剩，是促进 NASH的发展。然而，目前仍不清楚代谢应激是否以及如何直接调节NASH- 相关的肝脏损伤。我们最近的研究发现，细胞内的能量感受器AMP激活的蛋白激酶 (AMPK)在NASH中感知代谢应激并控制肝损伤。AMPK在营养过剩过程中的抑制 肥胖会促进NASH相关的肝损伤和纤维化。此外，我们还直接鉴定了AMPK 使酶原原天冬氨酸氨基转移酶-6磷酸化，并阻止其在肝脏中的切割和激活。此外， 初步研究表明，激活的caspase-6裂解Bcl-2家族蛋白以介导前馈 凋亡caspase级联中的通路。这些发现表明，一个新的AMPK-caspase-6-Bid轴可能 控制NASH中的肝损伤和随后的纤维化。我们假设AMPK感觉到新陈代谢压力并 控制caspase-6的激活，进而通过切割Bid介导NASH相关的肝损伤 肝细胞。我们将出于以下目的探讨这一假说。具体目标1将描述规则 以及caspase-6在NASH病理生理学中的作用。利用现有和新的转基因小鼠模型， 包括全局和条件性基因敲除小鼠，我们将彻底评估caspase-6在 NASH的发病机制，并检测BID是否介导了caspase-6的有害功能。特定目标 2将阐述AMPK-caspase-6-BID轴调节肝细胞死亡的分子机制。 拟议中的研究结果将揭开NASH相关性肝损伤和 确定新疗法开发的潜在靶点。

Project Summary Nonalcoholic fatty liver disease (NAFLD) has become a prevalent health risk. Nonalcoholic steatohepatitis (NASH), featured by hepatic steatosis, inflammation, liver injury, and fibrosis, could lead to the occurrence of cirrhosis and liver cancer, both of which require liver transplantation. Although NASH is reversible, there is no therapeutics that have been approved by FDA. The pathogenesis for this devastating disease remains poorly understood. Therefore, investigating the molecular mechanism underlying NASH pathogenesis and identifying potential therapeutic targets are of great significance. Liver injury caused by hepatocellular death is a cardinal feature of NASH and is typically characterized by the presence of ballooned hepatocytes on liver biopsy examination. In normal liver, hepatocyte apoptosis plays a key role in liver homeostasis, maintaining equilibrium between hepatocyte loss and replacement. However, pathological conditions including alcoholic or nonalcoholic steatohepatitis lead to extensive hepatocyte death and liver injury. Numerous studies suggest that hepatocellular death is the key event triggering the progression of NAFLD and the development of cirrhosis and liver cancer. Thus, understanding the molecular mechanisms by which hepatocellular death is controlled may lead to new treatments for NASH. Metabolic stress, such as overnutrition, is a major pathogenic factor promoting the development of NASH. However, it is still unclear whether and how metabolic stress directly regulates NASH- associated liver injury. Our recent study found that the intracellular energy sensor AMP-activated protein kinase (AMPK) senses metabolic stress and controls liver injury in NASH. The repression of AMPK during overnutrition and obesity promotes NASH-associated liver injury and fibrosis. Moreover, we identified that AMPK directly phosphorylates zymogen procaspase-6 and prevents its cleavage and activation in livers. Furthermore, preliminary studies suggest that active caspase-6 cleaves Bcl-2 family protein BID to mediate a feedforward pathway in the apoptotic caspase cascade. These findings indicate that a novel AMPK-caspase-6-BID axis may control liver injury and subsequent fibrosis in NASH. We hypothesize that AMPK senses metabolic stress and controls caspase-6 activation, which in turn mediates NASH-associated liver injury via cleaving BID in hepatocytes. We will explore this hypothesis with the following aims. Specific Aim 1 will delineate the regulation and function of caspase-6 in NASH pathophysiology. Using existing and new transgenic mouse models, including global and conditional knockout mice, we will thoroughly evaluate the role of caspase-6 in the pathogenesis of NASH, and examine whether BID mediates the deleterious function of caspase-6. Specific Aim 2 will elaborate the molecular mechanism by which the AMPK-caspase-6-BID axis regulates hepatocyte death. The findings from proposed studies will unravel a novel mechanism underlying NASH-associated liver injury and identify potential targets for the development of new therapy.