Metabolic regulation of cholestatic liver injury by D-2-hydroxyglutarate with the modulation of hepatic microenvironment and the mammalian target of rapamycin signaling.
Metabolic regulation of cholestatic liver injury by D-2-hydroxyglutarate with the modulation of hepatic microenvironment and the mammalian target of rapamycin signaling.
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DOI：
10.1038/s41419-022-05450-z
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发表时间：
2022-11-26
影响因子：
9
通讯作者：
Xiao, Yongtao
中科院分区：
文献类型：
--
作者：
Tian, Xinbei;Wang, Ying;Lu, Ying;Wu, Bo;Chen, Shanshan;Du, Jun;Cai, Wei;Xiao, Yongtao
胆道闭锁是一种新生儿胆汁淤积性肝病，伴有严重的肝内外胆管梗阻。由于缺乏早期诊断标志物和对其发病机制的了解有限，BA通常导致2年内死亡。因此，本研究的目的是发展早期诊断方法，并探讨潜在的发病机制，在BA肝损伤代谢组学。代谢组学和类器官联合能量代谢分析用于使用患者样本、小鼠肝脏类器官和斑马鱼模型获得对BA诊断和病理生物学的新见解。代谢组学研究显示，BA患者血浆和肝脏中D-2-羟基戊二酸（D-2-HG）水平显著升高，并与肝损伤和肝再生障碍密切相关。D-2-HG抑制肝内胆管衍生的肝类器官的生长和扩张。能量代谢分析表明，D-2-HG抑制线粒体呼吸和ATP合成酶，但它增加有氧糖酵解类器官。此外，D-2-HG暴露引起斑马鱼幼鱼肝脏变性。在机制上，D-2-HG抑制蛋白激酶B和雷帕霉素信号传导的哺乳动物靶标的活化。这些发现表明，D-2-HG可能代表一种新的非侵入性诊断生物标志物和一个潜在的治疗靶点的婴儿与BA。
Biliary atresia (BA) is a cholestatic liver disease in neonates with devastating obstructive intrahepatic and extrahepatic biliary ducts. Owing to the lack of an early diagnostic marker and limited understanding of its pathogenesis, BA often leads to death within 2 years. Therefore, this study aimed to develop early diagnostic methods and investigate the underlying pathogenesis of liver injury in BA using metabolomics. Metabolomics and organoid combined energy metabolism analysis was used to obtain new insights into BA diagnosis and pathobiology using patient samples, mice liver organoids, and a zebrafish model. Metabolomics revealed that D-2-hydroxyglutarate (D-2-HG) levels were significantly elevated in the plasma and liver of patients with BA and closely correlated with liver injuries and impaired liver regeneration. D-2-HG suppressed the growth and expansion of liver organoids derived from the intrahepatic biliary ducts. The energy metabolism analysis demonstrated that D-2-HG inhibited mitochondrial respiration and ATP synthase; however, it increased aerobic glycolysis in organoids. In addition, D-2-HG exposure caused liver degeneration in zebrafish larvae. Mechanistically, D-2-HG inhibited the activation of protein kinase B and the mammalian target of rapamycin signaling. These findings reveal that D-2-HG may represent a novel noninvasive diagnostic biomarker and a potential therapeutic target for infants with BA.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.9
作者：
Lampela, Hanna;Kosola, Silja;Pakarinen, Mikko P.
通讯作者：
Pakarinen, Mikko P.
DOI：
10.5500/wjt.v3.i3.36
发表时间：
2013-09-24
期刊：
World journal of transplantation
影响因子：
--
作者：
Fouraschen, Suomi Mg;de Ruiter, Petra E;de Jonge, Jeroen
通讯作者：
de Jonge, Jeroen
DOI：
10.1073/pnas.0404840101
发表时间：
2004-11-30
影响因子：
11.1
作者：
Rzem, R;Veiga-da-Cunha, M;Van Schaftingen, E
通讯作者：
Van Schaftingen, E
DOI：
10.1002/hep.29905
发表时间：
2018-09
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Bezerra JA;Wells RG;Mack CL;Karpen SJ;Hoofnagle JH;Doo E;Sokol RJ
通讯作者：
Sokol RJ