Alcohol-associated liver disease facilitates lobule scale metabolic reprogramming to modulate regeneration

酒精相关的肝病促进小叶尺度代谢重编程以调节再生

• 批准号: 10765601
• 负责人: Alexandra Rose Manchel
• 金额: $ 4.77万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2024-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10765601
• 关键词: Activities of Daily Living; Alcohol abuse; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Automobile Driving; Behavior; Cell Proliferation; Cells; Cessation of life; Chronic; Clinical; Compensation; Data; Disease; Disease Progression; Donor person; Enzymes; Equilibrium; Ethanol; Event; Excision; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Gluconeogenesis; Glucose; Glycolysis; Goals; Health; Hepatic; Hepatocyte; Homeostasis; Human; Impairment; Intervention; Light; Lipids; Liver; Liver diseases; Liver neoplasms; Living Donors; Lobule; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Natural regeneration; Nature; Operative Surgical Procedures; Organ; Partial Hepatectomy; Pathologic; Pathway interactions; Patients; Play; Population; Process; Proliferating; Proliferation Marker; Publications; Rattus; Recovery; Regenerative capacity; Regenerative response; Regulation; Research; Resected; Resolution; Rodent; Sampling; Slide; Specificity; Stains; Techniques; Testing; Tissue Sample; Tissues; Transplantation; Work; effective therapy; enzyme activity; fatty acid oxidation; gene function; genome-wide; human data; laser capture microdissection; lipid biosynthesis; liquid chromatography mass spectrometry; liver cell proliferation; liver injury; metabolomics; mortality; novel; regeneration potential; regenerative; restoration; single-cell RNA sequencing; standard care; therapeutic target; transcriptome sequencing; transcriptomics

PROJECT SUMMARY The mortality rate of liver disease due to alcohol abuse, is steadily increasing, necessitating early clinical intervention. Current intervention techniques, such as resection and transplantation, rely extensively on the liver's ability to regenerate. During the normal regenerative course, hepatocytes must not only proliferate but also metabolically compensate for lost tissue mass. However, during ALD progression, this proliferative ability is significantly diminished. There are additional detriments at the metabolic level, as zonation, or the spatial organization of metabolic processes across the liver lobule, becomes dysregulated with many key gluconeogenic and lipid metabolizing enzymes losing their spatial specificity. To date, little is known about the specific metabolic events allowing for hepatocellular proliferation during regeneration, and how metabolic reprogramming leads to diminished proliferation in ALD. Therefore, the goals of this project are to uncover the metabolic mechanisms driving heterogeneous, zonated hepatocyte populations to tissue mass restoration and to elucidate the metabolic reprogramming events impairing proper regeneration during ALD progression. Through this work, we aim to test two hypotheses: (1) during regeneration, at peak cellular proliferation, normally zonated metabolic gene expression is disrupted, leading to a reduction in metabolically compensating hepatocytes and a decrease in overall proliferative ability in ethanol-adapted livers; (2) there exists a set of pathological, zone-specific metabolic reprogramming events that can signify the extent of alcohol-associated, decompensated liver damage and hepatocyte proliferative ability at each stage of progressing ALD. The first hypothesis seeks to determine the relationship between spatial regulation and metabolic functionality of distinct hepatocyte populations during regeneration. This hypothesis will be tested using a chronic ethanol-fed rat model of partial hepatectomy, in which 70% of the liver is resected, to identify the relationship between metabolic gene transcription and function of heterogeneous hepatocyte populations, proliferating and metabolically compensating, during regeneration. The second hypothesis seeks to identify the metabolic reprogramming events occurring during progressive ALD in human patients. Extensive analyses of metabolomic and transcriptomic data from human tissue samples with progressing ALD will be performed to test this hypothesis. Both hypotheses will employ quantitative metabolic modelling approaches to make functional predictions about the enzymatic behavior of hepatocytes during health and disease, which will be compared to and tested against collected metabolomics data. Through this work, we seek to elucidate the mechanisms disrupting the tightly interconnected relationship between metabolic regulation and function during alcohol adaptation, and determine the metabolic reprogramming events occurring at each stage of progressing ALD.

项目概要 酗酒导致的肝病死亡率正在稳步上升，需要早期临床治疗 干涉。当前的干预技术，例如切除和移植，很大程度上依赖于 肝脏的再生能力。在正常的再生过程中，肝细胞不仅必须增殖，而且必须 还通过代谢补偿损失的组织质量。然而，在 ALD 进展过程中，这种增殖能力 明显减少。在代谢水平上还有其他损害，如分区或空间 肝小叶代谢过程的组织因许多关键的糖异生而失调 脂质代谢酶失去了空间特异性。迄今为止，人们对具体的代谢知之甚少。 再生过程中允许肝细胞增殖的事件，以及代谢重编程如何导致 ALD 增殖减少。因此，该项目的目标是揭示代谢 驱动异质、分区肝细胞群恢复组织质量和 阐明在 ALD 进展过程中损害正常再生的代谢重编程事件。 通过这项工作，我们的目标是测试两个假设：（1）在再生期间，在细胞增殖高峰期，通常 分区代谢基因表达被破坏，导致代谢补偿减少 肝细胞和乙醇适应肝脏的整体增殖能力下降； (2) 存在一组 病理性的、特定区域的代谢重编程事件可以表明与酒精相关的程度， ALD 进展的每个阶段都有失代偿性肝损伤和肝细胞增殖能力。 第一个假设旨在确定空间调节和代谢之间的关系 再生过程中不同肝细胞群的功能。该假设将通过慢性试验进行检验 乙醇喂养的部分肝切除大鼠模型，其中 70% 的肝脏被切除，以确定两者之间的关系 代谢基因转录与异源肝细胞群、增殖和功能之间的关系 在再生过程中进行代谢补偿。第二个假设旨在确定代谢 人类患者进行性 ALD 期间发生的重编程事件。代谢组学的广泛分析 来自患有进展性 ALD 的人体组织样本的转录组数据将用于测试这一点 假设。这两种假设都将采用定量代谢建模方法来使功能性 对健康和疾病期间肝细胞酶行为的预测，将与 并根据收集的代谢组学数据进行测试。通过这项工作，我们试图阐明其机制 破坏酒精期间代谢调节和功能之间紧密相连的关系 适应，并确定在 ALD 进展的每个阶段发生的代谢重编程事件。