Metabolic Landscape of the Mouse Liver by Quantitative (31) P Nuclear Magnetic Resonance Analysis of the Phosphorome.
Metabolic Landscape of the Mouse Liver by Quantitative (31) P Nuclear Magnetic Resonance Analysis of the Phosphorome.
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DOI：
10.1002/hep.31676
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Millet O
中科院分区：
文献类型：
--
作者：
Bernardo-Seisdedos G;Bilbao J;Fernández-Ramos D;Lopitz-Otsoa F;Gutierrez de Juan V;Bizkarguenaga M;Mateos B;Fondevila MF;Abril-Fornaguera J;Diercks T;Lu SC;Nogueiras R;Mato JM;Millet O
肝脏在体内所有代谢过程中起着核心作用。然而，肝脏代谢的精确表征往往被其固有的复杂性所掩盖。磷酸化代谢产物在所有合成代谢和分解代谢途径中占据重要地位。在这里，我们开发了一种基于31 P核磁共振（NMR）的方法，通过同时鉴定和定量多种亲水性和疏水性磷酸化代谢产物来研究肝脏“磷质组”。我们应用这种技术来定义罕见疾病先天性红细胞生成性卟啉症（CEP）小鼠模型以及两种众所周知的非酒精性脂肪性肝炎小鼠模型的肝脏代谢景观：一种遗传性蛋氨酸腺苷转移酶1A基因敲除小鼠，另一种饮食，喂食高脂肪胆碱缺乏饮食的小鼠。我们报告了磷酸化代谢物浓度的改变，这些代谢物是糖酵解、糖异生、戊糖磷酸途径、三羧酸循环和氧化磷酸化之间的平衡以及磷脂代谢和细胞凋亡的读数。此外，这些变化与主要的组织学特征相关：脂肪变性、细胞凋亡、铁沉积和纤维化。引人注目的是，用重新利用的药物环吡酮治疗改善了CEP小鼠的磷组学特征，这一效果反映在肝脏组织学的正常化上。总之，这些研究结果表明，基于NMR的磷组学可用于阐明肝损伤的代谢表型，并确定药物作用机制。
The liver plays a central role in all metabolic processes in the body. However, precise characterization of liver metabolism is often obscured by its inherent complexity. Phosphorylated metabolites occupy a prominent position in all anabolic and catabolic pathways. Here, we develop a 31P nuclear magnetic resonance (NMR)–based method to study the liver “phosphorome” through the simultaneous identification and quantification of multiple hydrophilic and hydrophobic phosphorylated metabolites. We applied this technique to define the metabolic landscape in livers from a mouse model of the rare disease disorder congenital erythropoietic porphyria (CEP) as well as two well‐known murine models of nonalcoholic steatohepatitis: one genetic, methionine adenosyltransferase 1A knockout mice, and the other dietary, mice fed a high‐fat choline‐deficient diet. We report alterations in the concentrations of phosphorylated metabolites that are readouts of the balance between glycolysis, gluconeogenesis, the pentose phosphate pathway, the tricarboxylic acid cycle, and oxidative phosphorylation and of phospholipid metabolism and apoptosis. Moreover, these changes correlate with the main histological features: steatosis, apoptosis, iron deposits, and fibrosis. Strikingly, treatment with the repurposed drug ciclopirox improves the phosphoromic profile of CEP mice, an effect that was mirrored by the normalization of liver histology. In conclusion, these findings indicate that NMR‐based phosphoromics may be used to unravel metabolic phenotypes of liver injury and to identify the mechanism of drug action.
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影响因子：
3.5
作者：
Blouin, Jean-Marc;Bernardo-Seisdedos, Ganeko;Richard, Emmanuel
通讯作者：
Richard, Emmanuel
DOI：
10.1016/0925-4439(93)90124-j
发表时间：
1993-11-25
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
BELL, JD;COX, IJ;URENJAK, J
通讯作者：
URENJAK, J
影响因子：
2.5
作者：
Lee, Wen-Hao;Tai, Wei-Chun;Wu, Po-Yuan
通讯作者：
Wu, Po-Yuan
DOI：
10.1152/ajpgi.00301.2011
发表时间：
2012-01-01
影响因子：
4.5
作者：
Kakisaka, Keisuke;Cazanave, Sophie C.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
5.7
作者：
Bishop, David F.;Clavero, Sonia;Desnick, Robert J.
通讯作者：
Desnick, Robert J.