Mannose metabolism as a regulator of hepatic stellate cell activation and fibrosis

甘露糖代谢作为肝星状细胞活化和纤维化的调节剂

• 批准号: 9885622
• 负责人: Jaime C Chu
• 金额: $ 37.81万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9885622
• 关键词: Address; Apoptosis; Attenuated; Automobile Driving; Biology; Catabolism; Cell Death; Cell Proliferation; Cells; Cellular biology; Child; Childhood; Cicatrix; Cirrhosis; Clinical; Congenital Disorders; Data; Diabetes Mellitus; Disease; Dose; Enzymes; Ethanol; Exposure to; Fibrosis; Genetic; Goals; Hepatic Stellate Cell; Hepatitis B Virus; Hepatocyte; Hepatology; Human; In Vitro; Isomerase; Lead; Link; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Mannose; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolic Pathway; Metabolism; Minor; Modeling; Mutation; Obesity; Pathway interactions; Phenotype; Public Health; Rattus; Regulation; Rodent; Rodent Model; Role; Supplementation; Testing; Therapeutic; Thioacetamide; Vitamin A; Zebrafish; attenuation; cancer cell; cell type; chronic liver disease; cohort; drug discovery; fibrogenesis; glycosylation; in vivo; inorganic phosphate; liver metabolism; liver transplantation; mutant; new therapeutic target; non-alcoholic fatty liver disease; novel; prevent; response; restoration; sugar

PROJECT SUMMARY Mannose metabolism as a regulator of hepatic stellate cell activation and fibrosis This proposal addresses the critical unmet need for effective anti-fibrotic therapies by elucidating an unexplored pathway regulating activation of the hepatic stellate cell (HSC), a resident perisinusoidal cell type that stores vitamin A in normal liver. However, among potential mechanisms driving HSC plasticity, sugar metabolism pathways have been largely overlooked. The role of mannose metabolism in HSC biology has not yet been examined, but recent high-impact studies, including ours (Shtraizent and DeRossi et al., eLife 2017), implicate mannose as a mediator of obesity, diabetes, and cancer. Mannose phosphate isomerase (MPI) is the key enzyme involved in catabolism of mannose; MPI mutation in humans leads to a congenital disorder of N- glycosylation characterized by early and progressive liver fibrosis in children. Our data and these clinical observations stimulated us to explore how the loss of MPI in this pediatric disorder leads to liver fibrosis. Our exciting data find that: 1) MPI is decreased during HSC activation and fibrosis in rodents and zebrafish in vivo, 2) decreased MPI correlates with advanced stages of liver fibrosis in human HBV and NAFLD cohorts, and 3) MPI depletion promotes HSC activation in human HSCs. Remarkably, mannose supplementation attenuates HSC activation in a dose-dependent manner. Our objective is to understand the regulatory role of mannose metabolism in HSCs and liver fibrosis. With the following aims, we will test our central hypotheses that mannose metabolism is a critical metabolic pathway mediating HSC activation and attenuation. Disruption of mannose metabolism, through loss of MPI, leads to HSC activation; conversely, exogeneous mannose supplementation can attenuate HSC activation and liver fibrosis in vivo. Specific Aims: Aim 1. Determine how MPI loss activates HSCs: By using primary rat HSCs and in vivo genetic zebrafish models, we will investigate the role of O-GlcNAcylation in HSC activation, determine the cell-specific effects of MPI-depletion, and test whether enhancing MPI activity can attenuate fibrogenesis following exposure to well-established HSC activators. Aim 2. Determine the efficacy of mannose supplementation in attenuating HSC activation in vitro and in vivo. This aim will use in vivo rodent models of fibrosis to investigate how mannose supplementation modulates the plasticity of HSC phenotypes and test the extent of mannose to attenuate liver fibrosis in vivo. Our long-term goal is to better understand the metabolic drivers of HSC activation to manipulate these fuel-generating mechanisms and attenuate liver fibrosis. We will leverage our expertise in the biology of a rare liver disease to advance our understanding of the metabolic regulation of HSC activation, and to establish how this overlooked pathway of mannose metabolism can regulate HSC plasticity. These studies are the first to investigate the antifibrotic roles of mannose supplementation and may reveal a novel target and accessible therapeutic approach to suppress liver fibrosis.

项目总结 甘露糖代谢作为肝星状细胞活化和纤维化的调节因子 这项建议通过阐明一种有效的抗纤维化疗法来解决尚未得到满足的关键需求 肝星状细胞(HSC)是一种驻留在肝窦周围的细胞类型，其调节激活的途径尚不清楚 将维生素A储存在正常肝脏中。然而，在推动HSC可塑性的潜在机制中，糖 新陈代谢途径在很大程度上被忽视了。甘露糖代谢在肝星状细胞生物学中的作用 尚未审查，但最近的高影响研究，包括我们的(Shtraizent和DeRossi等人，eLife 2017)， 甘露糖是肥胖、糖尿病和癌症的中介物。甘露糖磷酸异构酶(MPI)是 参与甘露糖分解代谢的关键酶；人类MPI突变导致先天性N- 以儿童早期和进行性肝纤维化为特征的糖基化。我们的数据和这些临床 观察促使我们探索MPI在这种儿科疾病中的丢失是如何导致肝纤维化的。我们的 令人兴奋的数据发现：1)在啮齿动物和斑马鱼体内，HSC激活和纤维化过程中MPI减少， 2)在人类乙肝和非酒精性脂肪肝队列中，MPI降低与晚期肝纤维化相关；3) MPI耗竭可促进人HSC的激活。值得注意的是，补充甘露糖可以减弱 HSC激活呈剂量依赖关系。我们的目标是了解甘露糖的调节作用。 肝干细胞的代谢与肝纤维化。有了以下目标，我们将测试我们的中心假设 甘露糖代谢是介导肝星状细胞激活和减弱的关键代谢途径。 通过丢失MPI破坏甘露糖代谢，导致HSC激活；反之， 外源性补充甘露糖可减轻体内HSC活化和肝纤维化。特定的 目的：目的：1.确定MPI缺失如何激活HSCs：通过使用原代大鼠HSCs和体内基因 在斑马鱼模型中，我们将研究O-GlcN酰化在HSC激活中的作用，确定细胞特异性 MPI耗竭的影响，并测试增强MPI活性是否可以减轻以下纤维化 接触成熟的HSC激活剂。目的2.测定补充甘露糖的疗效 降低体内、体外HSC活性。这一目标将使用体内的啮齿动物纤维化模型来研究 补充甘露糖如何调节HSC表型的可塑性，并测试甘露糖对 体内抗肝纤维化作用。我们的长期目标是更好地了解HSC的代谢驱动因素 激活以操纵这些燃料产生机制并减轻肝纤维化。我们将利用我们的 在一种罕见肝病的生物学方面的专业知识，以促进我们对HSC代谢调节的理解 并确定这一被忽视的甘露糖代谢途径如何调节HSC的可塑性。 这些研究是第一次调查甘露糖补充剂的抗纤维化作用，并可能揭示一种 抑制肝纤维化的新靶点和可获得的治疗方法。