Integrated Multiomics Reveals Glucose Use Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis.
Integrated Multiomics Reveals Glucose Use Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis.
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DOI：
10.1053/j.gastro.2020.12.008
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发表时间：
2021-04
期刊：
影响因子：
29.4
通讯作者：
Bataller R
中科院分区：
文献类型：
--
作者：
Massey V;Parrish A;Argemi J;Moreno M;Mello A;García-Rocha M;Altamirano J;Odena G;Dubuquoy L;Louvet A;Martinez C;Adrover A;Affò S;Morales-Ibanez O;Sancho-Bru P;Millán C;Alvarado-Tapias E;Morales-Arraez D;Caballería J;Mann J;Cao S;Sun Z;Shah V;Cameron A;Mathurin P;Snider N;Villanueva C;Morgan TR;Guinovart J;Vadigepalli R;Bataller R
我们最近发现，酒精性肝炎（AH）的特点是肝细胞的去分化和成熟功能的丧失。葡萄糖代谢在健康肝细胞中受到严格调节。我们推测AH可能导致肝脏的代谢重编程，包括葡萄糖代谢的失调。我们对AH或酒精性肝硬化患者的肝组织或肝切除术后的正常肝组织进行了综合代谢组学和转录组学分析。进行染色质免疫沉淀结合DNA测序的集中分析。在原代大鼠和人肝细胞以及HepG2细胞中进行了功能性体外研究。AH患者表现出特定的糖酵解/糖异生，三羧酸循环，单糖和二糖代谢的中间体水平的变化。对转录组和代谢组的综合分析显示，AH患者使用了替代能量途径、代谢物汇和瓶颈以及葡萄糖储存失调。在参与葡萄糖代谢的基因中，己糖激酶结构域1（HKDC 1）被确定为AH患者中上调最多的激酶。组蛋白活性启动子和增强子标记在HKDC 1基因组区域增加。高HKDC 1水平与急性肾损伤的发生和生存率降低相关。HKDC 1活性增加有助于葡萄糖-6-P和糖原在原代大鼠肝细胞中的积累。代谢酶的代谢物水平和信使RNA表达的改变表明AH中存在广泛的葡萄糖代谢重编程。HKDC1表达增加可能导致葡萄糖代谢失调，并代表AH的新生物标志物和治疗靶点。
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.
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影响因子：
16.6
作者：
Guo C;Ludvik AE;Arlotto ME;Hayes MG;Armstrong LL;Scholtens DM;Brown CD;Newgard CB;Becker TC;Layden BT;Lowe WL;Reddy TE
通讯作者：
Reddy TE
影响因子：
9.8
作者：
Dominguez, Marlene;Rincon, Diego;Bataller, Ramon
通讯作者：
Bataller, Ramon
影响因子：
4.8
作者：
Ludvik, Anton E.;Pusec, Carolina M.;Layden, Brian T.
通讯作者：
Layden, Brian T.
影响因子：
5.3
作者：
She, P;Shiota, H;Magnuson, MA
通讯作者：
Magnuson, MA
DOI：
10.1016/j.bbrc.2016.05.007
发表时间：
2016-06-10
影响因子：
3.1
作者：
Zhang, Zijian;Huang, Shanzhou;Zhou, Qi
通讯作者：
Zhou, Qi