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

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.

Automated summary

This study reveals the involvement of propionyl-CoA (Pro-CoA) metabolism in hepatocellular carcinoma (HCC) and its impact on HCC proliferation and energy metabolism. ALDH6A1-mediated Pro-CoA metabolism suppresses HCC proliferation by impairing energy metabolism. The metabolites derived from Pro-CoA metabolism serve as potential metabolic biomarkers for HCC diagnosis and treatment.