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

Published:November 30, 2022DOI:


      • 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.


      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.


      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.


      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


      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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        • Schulze K.
        • Imbeaud S.
        • Letouzé E.
        • Alexandrov L.B.
        • Calderaro J.
        • Rebouissou S.
        • et al.
        Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.
        Nat Genet. 2015; 47: 505-511
        • Jiang Y.
        • Sun A.
        • Zhao Y.
        • Ying W.
        • Sun H.
        • Yang X.
        • et al.
        Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma.
        Nature. 2019; 567: 257-261
        • Hoshida Y.
        • Nijman S.M.
        • Kobayashi M.
        • Chan J.A.
        • Brunet J.P.
        • Chiang D.Y.
        • et al.
        Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.
        Cancer Res. 2009; 69: 7385-7392
        • Bidkhori G.
        • Benfeitas R.
        • Klevstig M.
        • Zhang C.
        • Nielsen J.
        • Uhlen M.
        • et al.
        Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes.
        Proc Natl Acad Sci. 2018; 115
        • Satriano L.
        • Lewinska M.
        • Rodrigues P.M.
        • Banales J.M.
        • Andersen J.B.
        Metabolic rearrangements in primary liver cancers: cause and consequences.
        Nat Rev Gastroenterol Hepatol. 2019; 16: 748-766
        • Faubert B.
        • Solmonson A.
        • DeBerardinis R.J.
        Metabolic reprogramming and cancer progression.
        Science. 2020; : 368
        • Juhling F.
        • Hamdane N.
        • Crouchet E.
        • Li S.
        • El Saghire H.
        • Mukherji A.
        • et al.
        Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma.
        Gut. 2021; 70: 157-169
        • Beyoglu D.
        • Idle J.R.
        Metabolomic and lipidomic biomarkers for premalignant liver disease diagnosis and therapy.
        Metabolites. 2020; 10
        • Vander Heiden M.G.
        • DeBerardinis R.J.
        Understanding the intersections between metabolism and cancer biology.
        Cell. 2017; 168: 657-669
        • Huang Q.
        • Tan Y.
        • Yin P.
        • Ye G.
        • Gao P.
        • Lu X.
        • et al.
        Metabolic characterization of hepatocellular carcinoma using nontargeted tissue metabolomics.
        Cancer Res. 2013; 73: 4992-5002
        • Ferrarini A.
        • Di Poto C.
        • He S.
        • Tu C.
        • Varghese R.S.
        • Kara Balla A.
        • et al.
        Metabolomic analysis of liver tissues for characterization of hepatocellular carcinoma.
        J Proteome Res. 2019; 18: 3067-3076
        • Trefely S.
        • Lovell C.D.
        • Snyder N.W.
        • Wellen K.E.
        Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.
        Mol Metab. 2020; 38100941
        • Neinast M.
        • Murashige D.
        • Arany Z.
        Branched chain amino acids.
        Annu Rev Physiol. 2019; 81: 139-164
        • Wongkittichote P.
        • Ah Mew N.
        • Chapman K.A.
        Propionyl-CoA carboxylase - a review.
        Mol Genet Metab. 2017; 122: 145-152
        • Baumgartner M.R.
        • Horster F.
        • Dionisi-Vici C.
        • Haliloglu G.
        • Karall D.
        • Chapman K.A.
        • et al.
        Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia.
        Orphanet J Rare Dis. 2014; 9: 130
        • Ballhausen D.
        • Mittaz L.
        • Boulat O.
        • Bonafe L.
        • Braissant O.
        Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain.
        Neuroscience. 2009; 164: 578-587
        • Sass J.O.
        • Walter M.
        • Shield J.P.H.
        • Atherton A.M.
        • Garg U.
        • Scott D.
        • et al.
        3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
        J Inherit Metab Dis. 2011; 35: 437-442
        • Kiran S.
        • Murshedi F.A.
        • Jabri S.A.
        • Devi M.N.
        Alpha-methylacetoacetic aciduria in an Rh-negative pregnant Omani woman with breech presentation delivered with favourable outcome.
        J Obstet Gynaecol Can. 2019; 41: 492-494
        • Ho C.
        • Wang C.
        • Mattu S.
        • Destefanis G.
        • Ladu S.
        • Delogu S.
        • et al.
        AKT (v-akt murine thymoma viral oncogene homolog 1) and N-Ras (neuroblastoma ras viral oncogene homolog) coactivation in the mouse liver promotes rapid carcinogenesis by way of mTOR (mammalian target of rapamycin complex 1), FOXM1 (forkhead box M1)/SKP2.
        Hepatology. 2012; 55: 833-845
        • Stauffer J.K.
        • Scarzello A.J.
        • Andersen J.B.
        • De Kluyver R.L.
        • Back T.C.
        • Weiss J.M.
        • et al.
        Coactivation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors.
        Cancer Res. 2011; 71: 2718-2727
        • Perez D.M.
        The promise and problems of metabolic-based therapies for heart failure.
        Interv Cardiol (Lond). 2021; 13: 415-424
        • Collado M.S.
        • Armstrong A.J.
        • Olson M.
        • Hoang S.A.
        • Day N.
        • Summar M.
        • et al.
        Biochemical and anaplerotic applications of in vitro models of propionic acidemia and methylmalonic acidemia using patient-derived primary hepatocytes.
        Mol Genet Metab. 2020; 130: 183-196
        • Koppaka V.
        • Thompson D.C.
        • Chen Y.
        • Ellermann M.
        • Nicolaou K.C.
        • Juvonen R.O.
        • et al.
        Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application.
        Pharmacol Rev. 2012; 64: 520-539
        • Boyault S.
        • Rickman D.S.
        • de Reyniès A.
        • Balabaud C.
        • Rebouissou S.
        • Jeannot E.
        • et al.
        Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.
        Hepatology. 2007; 45: 42-52
        • Yamamoto M.
        • Xin B.
        • Nishikawa Y.
        Mouse model for hepatocellular carcinoma and cholangiocarcinoma originated from mature hepatocytes.
        Hepatic Stem Cells. 2019; : 221-236
        • Heindryckx F.
        • Colle I.
        • Van Vlierberghe H.
        Experimental mouse models for hepatocellular carcinoma research.
        Int J Exp Pathol. 2009; 90: 367-386
        • Hoxhaj G.
        • Manning B.D.
        The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism.
        Nat Rev Cancer. 2019; 20: 74-88
        • Molina-Sánchez P.
        • Ruiz de Galarreta M.
        • Yao M.A.
        • Lindblad K.E.
        • Bresnahan E.
        • Bitterman E.
        • et al.
        Cooperation between distinct cancer driver genes underlies intertumor heterogeneity in hepatocellular carcinoma.
        Gastroenterology. 2020; 159: 2203-2220.e2214
        • Reszko A.E.
        • Kasumov T.
        • Pierce B.A.
        • David F.
        • Hoppel C.L.
        • Stanley W.C.
        • et al.
        Assessing the reversibility of the anaplerotic reactions of the propionyl-CoA pathway in heart and liver.
        J Biol Chem. 2003; 278: 34959-34965
        • Currie E.
        • Schulze A.
        • Zechner R.
        • Walther Tobias C.
        • Farese Robert V.
        Cellular fatty acid metabolism and cancer.
        Cel Metab. 2013; 18: 153-161
        • Lee S.
        • Park C.
        • Yim J.
        Characterization of citrate synthase purified from Drosophila melanogaster.
        Mol Cell. 1997; 7: 599-604
        • Horswill A.R.
        • Escalante-Semerena J.C.
        Salmonella typhimurium LT2 catabolizes propionate via the 2-methylcitric acid cycle.
        J Bacteriol. 1999; 181: 5615-5623
        • Cheema-Dhadli S.
        • Leznoff C.C.
        • Halperin M.L.
        Effect of 2-methylcitrate on citrate metabolism: implications for the management of patients with propionic acidemia and methylmalonic aciduria.
        Pediatr Res. 1975; 9: 905-908
        • Czumaj A.
        • Szrok-Jurga S.
        • Hebanowska A.
        • Turyn J.
        • Swierczynski J.
        • Sledzinski T.
        • et al.
        The pathophysiological role of CoA.
        Int J Mol Sci. 2020; : 21
        • Hanahan D.
        • Weinberg Robert A.
        Hallmarks of cancer: the next generation.
        Cell. 2011; 144: 646-674
        • Hensley C.T.
        • Wasti A.T.
        • DeBerardinis R.J.
        Glutamine and cancer: cell biology, physiology, and clinical opportunities.
        J Clin Invest. 2013; 123: 3678-3684
        • Trefely S.
        • Lovell C.D.
        • Snyder N.W.
        • Wellen K.E.
        Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.
        Mol Metab. 2020; 38
        • Broadfield L.A.
        • Saigal A.
        • Szamosi J.C.
        • Hammill J.A.
        • Bezverbnaya K.
        • Wang D.
        • et al.
        Metformin-induced reductions in tumor growth involves modulation of the gut microbiome.
        Mol Metab. 2022; 61101498
        • Todisco S.
        • Convertini P.
        • Iacobazzi V.
        • Infantino V.
        TCA cycle rewiring as emerging metabolic signature of hepatocellular carcinoma.
        Cancers. 2019; 12
        • Brosnan M.E.
        • Letto J.
        Interorgan metabolism of valine.
        Amino Acids. 1991; 1: 29-35
        • Ericksen R.E.
        • Lim S.L.
        • McDonnell E.
        • Shuen W.H.
        • Vadiveloo M.
        • White P.J.
        • et al.
        Loss of BCAA catabolism during carcinogenesis enhances mTORC1 activity and promotes tumor development and progression.
        Cell Metab. 2019; 29: 1151-1165 e1156