Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, North Carolina.
Daniel Baugh Institute, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Gastroenterology. 2021 Apr;160(5):1725-1740.e2. doi: 10.1053/j.gastro.2020.12.008. Epub 2020 Dec 10.
BACKGROUND & AIMS: We recently showed that alcoholic hepatitis (AH) is characterized by dedifferentiation of hepatocytes and loss of mature functions. Glucose metabolism is tightly regulated in healthy hepatocytes. We hypothesize that AH may lead to metabolic reprogramming of the liver, including dysregulation of glucose metabolism.
We performed integrated metabolomic and transcriptomic analyses of liver tissue from patients with AH or alcoholic cirrhosis or normal liver tissue from hepatic resection. Focused analyses of chromatin immunoprecipitation coupled to DNA sequencing was performed. Functional in vitro studies were performed in primary rat and human hepatocytes and HepG2 cells.
Patients with AH exhibited specific changes in the levels of intermediates of glycolysis/gluconeogenesis, the tricarboxylic acid cycle, and monosaccharide and disaccharide metabolism. Integrated analysis of the transcriptome and metabolome showed the used of alternate energetic pathways, metabolite sinks and bottlenecks, and dysregulated glucose storage in patients with AH. Among genes involved in glucose metabolism, hexokinase domain containing 1 (HKDC1) was identified as the most up-regulated kinase in patients with AH. Histone active promoter and enhancer markers were increased in the HKDC1 genomic region. High HKDC1 levels were associated with the development of acute kidney injury and decreased survival. Increased HKDC1 activity contributed to the accumulation of glucose-6-P and glycogen in primary rat hepatocytes.
Altered metabolite levels and messenger RNA expression of metabolic enzymes suggest the existence of extensive reprogramming of glucose metabolism in AH. Increased HKDC1 expression may contribute to dysregulated glucose metabolism and represents a novel biomarker and therapeutic target for AH.
我们最近发现，酒精性肝炎（AH）的特征是肝细胞去分化和成熟功能丧失。健康肝细胞中的葡萄糖代谢受到严格调控。我们假设 AH 可能导致肝脏代谢重编程，包括葡萄糖代谢失调。
我们对来自 AH 或酒精性肝硬化患者或肝切除术正常肝组织的肝组织进行了综合代谢组学和转录组学分析。进行了染色质免疫沉淀结合 DNA 测序的聚焦分析。在原代大鼠和人肝细胞以及 HepG2 细胞中进行了功能体外研究。
AH 患者表现出糖酵解/糖异生、三羧酸循环以及单糖和二糖代谢中间产物水平的特定变化。转录组和代谢组的综合分析表明，AH 患者使用替代能量途径、代谢物汇和瓶颈以及葡萄糖储存失调。在涉及葡萄糖代谢的基因中，己糖激酶结构域包含 1 型（HKDC1）被鉴定为 AH 患者中上调最明显的激酶。HKDC1 基因区域的组蛋白活性启动子和增强子标记物增加。高 HKDC1 水平与急性肾损伤的发展和存活率降低有关。增加的 HKDC1 活性导致葡萄糖-6-P 和糖原在原代大鼠肝细胞中的积累。
代谢物水平和代谢酶的信使 RNA 表达的改变表明 AH 中存在广泛的葡萄糖代谢重编程。增加的 HKDC1 表达可能导致葡萄糖代谢失调，代表 AH 的一种新的生物标志物和治疗靶点。
