EphA2 in Non-Alcoholic Fatty Liver Disease

EphA2 在非酒精性脂肪肝中的作用

• 批准号: 10537048
• 负责人: Brenna H Pearson
• 金额: $ 4.68万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537048
• 关键词: Affect; Arterial Fatty Streak; Body Weight; Cell Adhesion; Cell Culture Techniques; Cells; Cirrhosis; Data; Development; Disease; Disease Progression; Enzymes; Eph Family Receptors; EphA Receptors; EphA2 Receptor; Ephrin B Receptor; Ephrins; Event; Family; Fatty Liver; Fibrosis; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Human; Inflammation; Knock-out; Knockout Mice; Left; Ligands; Lipids; Lipoproteins; Liver; Liver Failure; Mediating; Metabolism; Mitochondria; Modeling; Mus; Neoplasm Metastasis; Nonesterified Fatty Acids; Pathogenesis; Patients; Pattern; Phosphorylation; Phosphotransferases; Population; Primary carcinoma of the liver cells; Process; Receptor Protein-Tyrosine Kinases; Role; Signal Transduction; Single Nucleotide Polymorphism; Testing; Therapeutic; Tissues; Tyrosine; Viral; Work; axon guidance; cell type; chronic liver disease; fatty acid oxidation; feeding; knock-down; leukocyte homing; liver function; liver inflammation; liver injury; mammalian genome; migration; mouse model; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; overexpression; preclinical trial; protein expression; response; uptake

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis driven by enhanced free fatty acid (FFA) uptake and lipid synthesis with reduced lipid clearance through mitochondrial fatty acid oxidation and lipoprotein export. Excessive hepatic lipid accumulation can cause lipotoxicity, which promotes local inflammation, hepatocyte ballooning, and fibrosis. This process leads to the development of nonalcoholic steatohepatitis (NASH), that can further progress to cirrhosis, liver failure, or hepatocellular carcinoma if left unchecked. Current treatments for NAFLD/NASH seek to either reduce hepatic steatosis or diminish the fibrosis response that drives NASH development. While these treatments have shown great promise in pre-clinical trials, they have yet to provide a clear therapeutic benefit. The Eph family of receptor tyrosine kinases, the largest family in the mammalian genome, interact with Eph receptor-interacting (ephrin) ligands on adjacent cells to mediate cell adhesion/repulsion signaling during axonal guidance, tissue patterning, leukocyte homing, and metastasis. Differential ligand-dependent and ligand- independent phosphorylation events appear to mediate these often-inverse functions of EphA2 signaling. EphA2 interactions with ephrinA1 on an adjacent cell promote tyrosine autophosphorylation (Y588, Y772) and intrinsic kinase activity, resulting in the inhibition of proliferation and migration. In the absence of ligand, EphA2 can become phosphorylated on S897, classically by Akt, resulting in enhanced proliferation and migration through largely unknown mechanisms. Work from our lab demonstrated EphA2 expression in multiple cell types and EphA2 deletion reduces atherosclerotic plaque formation. Our preliminary data show that EphA2 knockout mice show significantly reduced liver weight/body weight ratios following high fat diet feeding associated with diminished hepatosteatosis and reduced inflammation. Furthermore, C57Bl/6J mice treated with a high fat diet for 8 weeks show enhanced expression of the EphA2 ligand ephrinA1, along with enhanced markers of EphA2 ligand-dependent signaling. In contrast, both NASH patients and mouse models of NASH show decreased ephrinA1 expression and enhanced markers of EphA2 ligand-independent signaling. Therefore, we hypothesize that ligand-dependent EphA2 signaling serves as an initial protective mechanism in early NAFLD that weakens as the disease progresses. Using a combination of cell culture and mouse models, we will determine the role of EphA2/EphrinA1 expression and signaling in lipid homeostasis and metabolism (Aim 1), and determine the role of EphA2/EphrinA1 expression and signaling in NAFLD/NASH progression (Aim 2). If successful, these studies will elucidate a novel role for EphA2 signaling in NAFLD/NASH pathogenesis and may provide a novel therapeutic target to reduce liver damage in NAFLD/NASH.

项目概要 非酒精性脂肪性肝病（NAFLD）的特点是游离脂肪增加驱动的肝脂肪变性 酸（FFA）摄取和脂质合成，通过线粒体脂肪酸氧化和减少脂质清除 脂蛋白输出。肝脏脂质堆积过多可引起脂毒性，促进局部 炎症、肝细胞膨胀和纤维化。这个过程导致了非酒精饮料的发展 脂肪性肝炎 (NASH)，如果不治疗，可能会进一步发展为肝硬化、肝功能衰竭或肝细胞癌 未经检查。目前 NAFLD/NASH 的治疗方法旨在减少肝脏脂肪变性或减少纤维化 驱动 NASH 发展的反应。虽然这些治疗方法在临床前试验中显示出巨大的希望， 它们尚未提供明确的治疗益处。 受体酪氨酸激酶 Eph 家族是哺乳动物基因组中最大的家族，与 Eph 相互作用 相邻细胞上的受体相互作用（肝配蛋白）配体在轴突过程中介导细胞粘附/排斥信号传导 引导、组织模式、白细胞归巢和转移。配体依赖性和配体依赖性的区别 独立的磷酸化事件似乎介导了 EphA2 信号传导的这些通常相反的功能。埃夫A2 与相邻细胞上的 ephrinA1 相互作用促进酪氨酸自磷酸化（Y588、Y772）和内在 激酶活性，导致增殖和迁移的抑制。在没有配体的情况下，EphA2 可以 通常由 Akt 在 S897 上磷酸化，从而通过以下方式增强增殖和迁移： 很大程度上未知的机制。我们实验室的工作证明了 EphA2 在多种细胞类型中表达， EphA2 缺失可减少动脉粥样硬化斑块的形成。我们的初步数据显示 EphA2 基因敲除小鼠 显示高脂肪饮食喂养后肝脏重量/体重比显着降低 减少肝脂肪变性并减少炎症。此外，C57Bl/6J 小鼠接受高脂肪饮食治疗 持续 8 周显示 EphA2 配体 ephrinA1 的表达增强，以及 EphA2 标记物增强 配体依赖性信号传导。相比之下，NASH 患者和 NASH 小鼠模型均表现出下降 ephrinA1 表达和增强的 EphA2 配体独立信号传导标记。因此，我们 假设配体依赖性 EphA2 信号作为早期的初始保护机制 NAFLD 随着疾病的进展而减弱。结合细胞培养和小鼠模型， 我们将确定 EphA2/EphrinA1 表达和信号传导在脂质稳态和代谢中的作用 （目标 1），并确定 EphA2/EphrinA1 表达和信号传导在 NAFLD/NASH 进展中的作用（目标 2）。如果成功，这些研究将阐明 EphA2 信号在 NAFLD/NASH 发病机制中的新作用 可能为减少 NAFLD/NASH 的肝损伤提供新的治疗靶点。