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 酒精滥用导致的肝病死亡率正在稳步上升，需要早期临床治疗。 干预目前的干预技术，如切除和移植，广泛依赖于 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， 也代谢补偿失去的组织质量。然而，在ALD进展过程中，这种增殖能力是 大大减少。在代谢水平上还有其他的限制，如地带性或空间性。 肝小叶代谢过程的组织，变得失调，许多关键的致炎性疾病， 以及脂质代谢酶失去其空间特异性。到目前为止，人们对特定的代谢产物知之甚少。 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 减少ALD的增殖。因此，本项目的目标是揭示代谢 驱动异质性、带状肝细胞群恢复组织块和 阐明ALD进展期间损害适当再生的代谢重编程事件。 通过这项工作，我们的目的是测试两个假设：（1）在再生过程中，在高峰细胞增殖，正常 带状代谢基因表达被破坏，导致代谢补偿减少， 肝细胞和整体增殖能力降低乙醇适应肝脏;（2）存在一组 病理性的、区域特异性的代谢重编程事件，这些事件可以表明酒精相关的， 在ALD进展的各个阶段，失代偿性肝损害和肝细胞增殖能力。 第一个假说试图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体的功能。这一假设将使用慢性 乙醇喂养的大鼠模型的部分肝切除术，其中70%的肝脏被切除，以确定关系 代谢基因转录与异质性肝细胞群体的功能之间的关系， 在再生过程中进行代谢补偿。第二个假设试图确定代谢 在人类患者中进行性ALD期间发生的重编程事件。代谢组学的广泛分析 并且将进行来自患有进展性ALD的人类组织样本的转录组学数据以测试这一点。 假说.这两种假设都将采用定量代谢建模方法， 关于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，我们试图阐明的机制， 破坏了酒精代谢调节和功能之间紧密联系的关系， 适应，并确定在ALD进展的每个阶段发生的代谢重编程事件。