A novel pathway controls liver injury in NASH

控制 NASH 肝损伤的新途径

• 批准号: 10652652
• 负责人: Peng Zhao
• 金额: $ 51.92万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-23 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652652
• 关键词: 5' -AMP-activated protein kinase; Adopted; Affect; Alcoholic steatohepatitis; Amino Acids; Apoptosis; Apoptotic; Attenuated; BCL2 gene; BID protein; CASP3 gene; CASP6 gene; CASP8 gene; Caspase; Cell Death; Cell Line; Cells; Cessation of life; Choline Deficiency; Cirrhosis; Classification; Data; Development; Diet; Disease; Energy Metabolism; Enzyme Precursors; Equilibrium; Event; FDA approved; Family member; Fatty Liver; Fibrosis; Foundations; Functional disorder; Goals; Health; HepG2; Hepatic Stellate Cell; Hepatocyte; High Fat Diet; Homeostasis; Human; In Vitro; Inflammation; Knock-out; Knockout Mice; Lead; Liver; Liver Fibrosis; Malignant neoplasm of liver; Mediating; Metabolic; Metabolic Control; Metabolic stress; Molecular; Mus; Obesity; Overnutrition; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phosphorylation; Physiology; Play; Prevalence; Primary carcinoma of the liver cells; Protein Family; Regulation; Repression; Research; Risk; Role; Science; Signal Transduction; Therapeutic; Transgenic Mice; Virulence Factors; conditional knockout; cytochrome c; drug development; effective therapy; fibrogenesis; in vivo; islet amyloid polypeptide; knock-down; liver biopsy; liver injury; liver transplantation; metabolic phenotype; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; nutrition; prevent; sensor; stellate cell; therapeutic development; therapeutic target

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.

项目摘要 非酒精性脂肪肝（NAFLD）已成为一种普遍的健康风险。非酒精性脂肪肝炎 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，两者都需要肝移植。虽然NASH是可逆的，但没有 FDA批准的治疗方法。这种毁灭性疾病的发病机制仍然不清楚 明白因此，研究NASH发病机制的分子机制和鉴定NASH的分子机制是非常重要的。 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一个主要的 NASH的特征，通常以肝活检中存在气球样肝细胞为特征 考试在正常肝脏中，肝细胞凋亡在维持肝脏稳态，维持平衡中起着关键作用 肝细胞丧失和替代之间的联系然而，病理条件，包括酒精或非酒精 脂肪性肝炎导致广泛肝细胞死亡和肝损伤。许多研究表明，肝细胞 死亡是引发NAFLD进展以及肝硬化和肝癌发展的关键事件。 因此，了解控制肝细胞死亡的分子机制可能会导致新的 NASH的治疗代谢应激，如营养过剩，是促进糖尿病的主要致病因素。 NASH的发展。然而，目前尚不清楚代谢应激是否以及如何直接调节NASH。 相关肝损伤。我们最近的研究发现，细胞内能量传感器AMP激活的蛋白激酶 AMPK能够感知代谢应激并控制NASH中的肝损伤。营养过剩时AMPK的抑制 肥胖会促进NASH相关的肝损伤和纤维化。此外，我们直接鉴定了AMPK， 磷酸化酶原半胱氨酸天冬氨酸蛋白酶原-6并阻止其在肝脏中的裂解和活化。此外，委员会认为， 初步研究表明，活性caspase-6切割Bcl-2家族蛋白BID，介导前馈 凋亡caspase级联反应中的信号通路。这些发现表明一种新的AMPK-半胱天冬酶-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感知代谢应激， 控制半胱天冬酶-6活化，后者又通过裂解BID介导NASH相关的肝损伤。 肝细胞我们将探讨这个假设与以下目标。具体目标1将描述该法规 caspase-6在NASH病理生理中的作用。使用现有的和新的转基因小鼠模型， 包括整体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，并检查BID是否介导半胱天冬酶-6的有害功能。具体目标 2将阐述AMPK-半胱天冬酶-6-BID轴调节肝细胞死亡的分子机制。 拟议研究的结果将揭示NASH相关肝损伤的新机制， 为新疗法的开发确定潜在的靶点。