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.

项目摘要 由于酗酒而导致的肝病的死亡率正在稳步增加，需要早期临床 干涉。当前的干预技术，例如切除和移植，广泛依赖于 肝脏再生能力。在正常再生过程中，肝细胞不仅必须增殖，而且必须 还可以通过代谢补偿损失的组织质量。但是，在ALD进展过程中，这种增殖能力是 大幅减少。作为分区或空间，在代谢水平上还有其他损害 整个肝脏小叶的代谢过程的组织，与许多关键糖原发生失调 和脂质代谢酶失去空间特异性。迄今为止，对特定代谢知之甚少 允许再生期间肝细胞增殖的事件，以及代谢重编程如何导致 ALD的增殖减少。因此，该项目的目标是揭示代谢 驱动异质，分区的肝细胞种群进行组织质量恢复和到 阐明代谢重编程事件会损害ALD进展过程中适当再生的情况。 通过这项工作，我们旨在检验两个假设：（1）在再生期间，在峰值细胞增殖下，通常 分区的代谢基因表达被破坏，导致代谢补偿的减少 肝细胞和适应乙醇适应的肝脏的总体增殖能力降低； （2）有一组 病理，区域特异性的代谢重编程事件，可以表示酒精相关的程度， 在进展ALD的每个阶段，肝脏损伤和肝细胞增殖能力都具有代偿性。 第一个假设旨在确定空间调节与代谢之间的关系 再生过程中不同肝细胞种群的功能。该假设将使用慢性进行检验 部分肝切除术的乙醇喂养的大鼠模型，其中70％的肝脏被切除，以识别这种关系 在异质肝细胞种群的代谢基因转录和功能之间，增殖和 在再生过程中代谢补偿。第二个假设旨在识别代谢 重编程事件在人类患者的进行性ALD期间发生。代谢组的广泛分析 将执行来自人体组织样品的转录组数据，以测试这一点 假设。这两个假设都将采用定量代谢建模方法来发挥功能 关于健康和疾病期间肝细胞酶促行为的预测，这将与 并针对收集的代谢组学数据进行了测试。通过这项工作，我们试图阐明机制 破坏代谢调节与酒精期间的功能之间紧密相互联系的关系 适应，并确定在进步ALD的每个阶段发生的代谢重编程事件。