Decreased propionyl-CoA metabolism facilitates metabolic reprogramming and promotes hepatocellular carcinoma
Decreased propionyl-CoA metabolism facilitates metabolic reprogramming and promotes hepatocellular carcinoma
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丙酰辅酶A代谢减少促进代谢重编程并促进肝细胞癌
DOI：
10.1016/j.jhep.2022.11.017
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发表时间：
2023-02-22
影响因子：
25.7
通讯作者：
Huang, Zan
中科院分区：
文献类型：
--
作者：
Sun, Jiaqi;Ding, Jun;Huang, Zan
背景与目的：肝细胞癌（HCC）中多种代谢物的改变是代谢重编程的特征。然而，大多数代谢物，包括丙酰辅酶A（Pro-CoA），在代谢重编程和肝癌发生中的作用仍然难以捉摸。方法：采用TCGA数据和HCC标本，分析ALDH 6A 1介导的Pro-CoA代谢及其与HCC的相关性。通过靶向质谱法测定多种代谢物。在HCC细胞系以及异种移植裸小鼠模型和原发性肝癌小鼠模型中评估ALDH 6A 1产生的Pro-CoA在HCC中的作用。非靶向代谢组学和有针对性的能量代谢组学分析，以及多个生化分析，performed.Results：减少前辅酶A及其衍生物丙酰-L-肉碱由于ALDH 6A 1下调与肝癌密切相关。在功能上，ALDH 6A 1介导的Pro-CoA代谢抑制体外HCC增殖并损害小鼠肝癌发生。醛脱氢酶活性对于ALDH 6A 1的这种功能是必不可少的，而Pro-CoA羧化酶通过消除Pro-CoA来拮抗ALDH 6A 1的功能。从机制上讲，ALDH 6A 1导致癌症中中心碳代谢的特征性富集和能量代谢受损：ALDH 6A 1产生的Pro-CoA抑制柠檬酸合酶活性，随后减少三羧酸循环通量，损害线粒体呼吸和膜电位，并减少ATP产生。结论：ALDH 6A 1介导的Pro-CoA代谢的下降参与了肝细胞的代谢重建，促进了肝癌的发生。Pro-CoA、丙酰-L-肉碱和2-甲基柠檬酸可能成为HCC诊断和治疗的新的代谢生物标志物。辅酶A原代谢可能为开发抗肝癌的新策略提供潜在靶点。(c)2022年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Alterations of multiple metabolites characterize distinct features of metabolic reprograming in hepatocellular carcinoma (HCC). However, the role of most metabolites, including propionyl-CoA (Pro-CoA), in metabolic reprogramming and hepatocarcinogenesis remains elusive. In this study, we aimed to dissect how Pro-CoA metabolism affects these processes.Methods: TCGA data and HCC samples were used to analyze ALDH6A1-mediated Pro-CoA metabolism and its correlation with HCC. Multiple metabolites were assayed by targeted mass spectrometry. The role of ALDH6A1-generated Pro-CoA in HCC was evaluated in HCC cell lines as well as xenograft nude mouse models and primary liver cancer mouse models. Non-targeted metabolomic and targeted energy metabolomic analyses, as well as multiple biochemical assays, were performed.Results: Decreases in Pro-CoA and its derivative propionyl-L-carnitine due to ALDH6A1 downregulation were tightly associated with HCC. Functionally, ALDH6A1-mediated Pro-CoA metabolism suppressed HCC proliferation in vitro and impaired hep-atocarcinogenesis in mice. The aldehyde dehydrogenase activity was indispensable for this function of ALDH6A1, while Pro-CoA carboxylases antagonized ALDH6A1 function by eliminating Pro-CoA. Mechanistically, ALDH6A1 caused a signature enrichment of central carbon metabolism in cancer and impaired energy metabolism: ALDH6A1-generated Pro-CoA suppressed citrate synthase activity, which subsequently reduced tricarboxylic acid cycle flux, impaired mitochondrial respiration and membrane potential, and decreased ATP production. Moreover, Pro-CoA metabolism generated 2-methylcitric acid, which mimicked the inhibitory effect of Pro-CoA on citrate synthase and dampened mitochondrial respiration and HCC proliferation.Conclusions: The decline of ALDH6A1-mediated Pro-CoA metabolism contributes to metabolic remodeling and facilitates hep-atocarcinogenesis. Pro-CoA, propionyl-L-carnitine and 2-methylcitric acid may serve as novel metabolic biomarkers for the diag-nosis and treatment of HCC. Pro-CoA metabolism may provide potential targets for development of novel strategies against HCC.(c) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.