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Decreased propionyl-CoA metabolism facilitates metabolic reprogramming and promotes hepatocellular carcinoma

Published:November 30, 2022DOI:https://doi.org/10.1016/j.jhep.2022.11.017

      Highlights

      • ALDH6A1 downregulation mediates the decline in propionyl-CoA metabolism that facilitates hepatocarcinogenesis.
      • Propionyl-CoA and 2-methylcitric acid suppress citrate synthase activity contributing to metabolic reprogramming in HCC.
      • Propionyl-CoA, propionyl-L-carnitine and 2-methylcitric acid may serve as novel metabolic biomarkers in HCC.

      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 hepatocarcinogenesis 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 hepatocarcinogenesis. Pro-CoA, propionyl-L-carnitine and 2-methylcitric acid may serve as novel metabolic biomarkers for the diagnosis and treatment of HCC. Pro-CoA metabolism may provide potential targets for development of novel strategies against HCC.

      Impact and implications

      Our study presents new insights on the role of propionyl-CoA metabolism in metabolic reprogramming and hepatocarcinogenesis. This work has uncovered potential diagnostic and predictive biomarkers, which could be used by physicians to improve clinical practice and may also serve as targets for the development of therapeutic strategies against HCC.

      Graphical abstract

      Keywords

      Linked Article

      • Novel oncometabolites and metabolic checkpoints involved in hepatocellular carcinoma development
        Journal of Hepatology
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          The study of metabolic reprogramming in cancer cells has deep roots in cancer biology research. Metabolic reprogramming refers to canonical metabolic pathways whose activity is suppressed or enhanced in cancer cells. The first metabolic alteration of cancer cells was described by Otto Warburg nearly a century ago and is now well known as the “Warburg effect”. The Warburg effect describes the tendency of cancer cells to consume large amounts of glucose via glycolysis, even in the presence of oxygen.
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