The Lysosomal-Mitochondrial Axis in Nonalcoholic Fatty Liver Disease

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)是全球慢性肝病的主要原因，但其发病机制仍知之甚少。线粒体功能受损在很大程度上被认为是导致这种疾病进展的核心异常。存在的中心问题是，什么事件将肝细胞中过多的脂肪堆积与线粒体功能障碍联系起来。因此，这项建议的总体目标是确定导致NAFLD线粒体功能障碍和疾病进展的细胞和分子机制。基于大量的初步数据，我们提出了一个新的中心假设，即肝脏中过多的游离脂肪酸积累会导致线粒体功能受损和NAFLD的进展，这是通过调节Bcl2家族成员来触发溶酶体通透性的。我们现在将使用电流和互补、分子、生化和细胞生物学的方法来进一步探讨NAFLD的溶酶体-线粒体轴。我们的建议有三个具体目标。首先，我们将在NAFLD的体外和体内模型以及NAFLD的人类标本和对照个体中识别和操纵启动溶酶体通透性的新的细胞内靶点。其次，我们将在NAFLD和无细胞系统的模型中从分子上定义溶酶体-线粒体轴。最后，我们将在NAFLD的体外组织模型和体内饮食小鼠模型中确定抑制溶酶体通透性和组织蛋白酶B激活是否可以防止肝脏损伤和纤维化。该提案在技术和概念上都是创新的，因为它使用尖端技术测试了脂质诱导的肝脏毒性的新概念。此外，由于非脂肪组织中游离脂肪酸过度积累所导致的脂毒性与其他人类肝病的发病机制有关，包括慢性丙型肝炎、酒精性脂肪性肝炎和血色素沉着症，以及其他疾病，如II型糖尿病和肥胖相关性心脏病，这项建议的结果不仅可能为这些疾病的发病机制带来新的见解，还可能转化为治疗这些疾病的新治疗策略(例如，使用药理上的Bax或组织蛋白酶B抑制剂)。

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide, yet its pathogenesis remains poorly understood. Impaired mitochondrial function is largely thought to be a core abnormality responsible for disease progression in this condition. The central question extant is what events link excessive lipid accumulation in liver cells to mitochondrial dysfunction. Thus, the overall objective of this proposal is to define the cellular and molecular mechanisms contributing to mitochondrial dysfunction and disease progression in NAFLD. Based on extensive preliminary data, we propose the novel CENTRAL HYPOTHESIS that excessive free fatty acids accumulation in the liver results in impaired mitochondrial function and NAFLD progression by triggering lysosomal permeabilization via regulation of the Bcl-2 family members We will now employ current and complementary, molecular, biochemical and cell biological approaches to further explore the lysosomal - mitochondrial axis in NAFLD. Our proposal has three SPECIFIC AIMS. FIRST, we will identify and manipulate novel intracellular targets that initiate lysosomal permeabilization in in-vitro and in-vivo models of NAFLD as well as human specimens of NAFLD and control individuals. SECOND, we will molecularly define the lysosomal - mitochondrial axis in models of NAFLD and cell free systems. FINALLY, we will determine if inhibition of lysosomal permeabilization and cathepsin B activation prevent liver injury and fibrosis in an in-vitro tissue model and in-vivo dietary murine models of NAFLD. The proposal is innovative technically and conceptually as it tests new concepts for lipid induced hepatotoxicity using sophisticated technologies. Moreover, because lipotoxicity as a result of over-accumulation of free fatty acids in non-adipose tissues has been implicated in the pathogenesis of other human liver diseases including chronic hepatitis C infection, alcoholic steatohepatitis and hemochromatosis, as well as other diseases such as type II diabetes and obesity associated heart disease the results of this proposal may not only bring new insights to the mechanisms underlying these conditions, but also could translate into new therapeutic strategies to treat them (e.g. the use of pharmacological Bax or cathepsin B inhibitors).