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

项目总结 由于酗酒导致的肝病死亡率正在稳步上升，因此需要及早进行临床治疗。 干预。目前的介入技术，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，而且 也可以在新陈代谢上补偿丢失的组织质量。然而，在ALD进展过程中，这种增殖能力是 显著减少了。在新陈代谢水平上还有额外的损害，如分区，或空间 跨肝小叶的代谢过程的组织，由于许多关键的糖异生而变得失调 和脂代谢酶失去其空间特异性。到目前为止，人们对特定新陈代谢知之甚少。 在再生过程中允许肝细胞增殖的事件，以及代谢重新编程如何导致 ALD增殖率降低。因此，这个项目的目标是揭示新陈代谢 推动异质、带状肝细胞群组织质量恢复和 阐明ALD进展过程中影响正常再生的代谢重编程事件。 通过这项工作，我们的目标是检验两个假设：(1)在再生过程中，细胞增殖高峰期，正常 区带代谢基因表达中断，导致代谢性补偿减少 肝细胞和乙醇适应的肝脏整体增殖能力下降；(2)存在一组 病理性的、特定于区域的代谢重新编程事件，可以表示与酒精相关的程度， ALD进展各阶段肝损伤失代偿性及肝细胞增殖能力。 第一个假设试图确定空间调节和新陈代谢之间的关系 不同的肝细胞群在再生过程中的功能。这一假设将用一种慢性的 乙醇喂养的大鼠肝部分切除模型，其中切除70%的肝脏，以确定关系 代谢基因转录与异质肝细胞群功能之间的关系 代谢补偿，在再生过程中。第二种假说试图确定新陈代谢 人类患者进展性ALD期间发生的重新编程事件。代谢组学的广泛分析 从进展中的ALD的人体组织样本中提取的转录数据将用于测试这一点 假设。这两个假说都将使用定量代谢模型方法来使 对健康和疾病期间肝细胞酶行为的预测，将与 并与收集的代谢组学数据进行对比测试。通过这项工作，我们试图阐明这种机制 打乱酒精过程中代谢调节和功能之间紧密联系的关系 适应，并确定在进展的ALD的每个阶段发生的代谢重新编程事件。

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.