A novel pathway controls liver injury in NASH

控制 NASH 肝损伤的新途径

基本信息

批准号：
10500991
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
项目类别：
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/10500991
关键词：
5&apos -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 Cirrhosis 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 Protein Kinase 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

项目摘要

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.

项目概要非酒精性脂肪肝（NAFLD）已成为一种普遍的健康风险。非酒精性脂肪性肝炎 NASH（NASH）以肝脂肪变性、炎症、肝损伤和纤维化为特征，可导致以下疾病的发生：肝硬化和肝癌，两者都需要肝移植。 NASH虽然是可逆的，但目前还没有已获得 FDA 批准的治疗方法。这种毁灭性疾病的发病机制仍不清楚明白了。因此，研究 NASH 发病机制的分子机制并确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主要原因 NASH 的特征，通常以肝活检中出现气球样肝细胞为特征考试。在正常肝脏中，肝细胞凋亡在肝脏稳态、维持平衡中起着关键作用肝细胞丢失和替代之间。然而，包括酒精或非酒精在内的病理状况脂肪性肝炎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带来新的发现。 NASH 的治疗。代谢应激，例如营养过剩，是促进疾病的主要致病因素。 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- 相关的肝损伤。我们最近的研究发现细胞内能量传感器 AMP 激活蛋白激酶 (AMPK) 感知代谢应激并控制 NASH 中的肝损伤。营养过剩期间 AMPK 的抑制肥胖会促进 NASH 相关的肝损伤和纤维化。此外，我们直接识别出 AMPK 磷酸化酶原 procaspase-6 并防止其在肝脏中裂解和激活。此外，初步研究表明，活性 caspase-6 裂解 Bcl-2 家族蛋白 BID 以介导前馈凋亡 caspase 级联中的途径。这些发现表明新的 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 能够感知代谢压力并控制 caspase-6 激活，进而通过裂解 BID 介导 NASH 相关肝损伤肝细胞。我们将出于以下目的探索这一假设。具体目标 1 将描述监管 Caspase-6 在 NASH 病理生理学中的作用。使用现有的和新的转基因小鼠模型，包括全局和条件敲除小鼠，我们将彻底评估caspase-6在 NASH 的发病机制，并检查 BID 是否介导 caspase-6 的有害功能。具体目标图2将详细阐述AMPK-caspase-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确定开发新疗法的潜在目标。