Active pyruvate dehydrogenase and impaired gluconeogenesis in orthotopic hepatomas of rats.
Cancer metabolism
Glycerol
Hepatocellular carcinoma
Pyruvate carboxylase
Pyruvate dehydrogenase
Tricarboxylic acid cycle
Journal
Metabolism: clinical and experimental
ISSN: 1532-8600
Titre abrégé: Metabolism
Pays: United States
ID NLM: 0375267
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
14
08
2019
revised:
27
09
2019
accepted:
07
10
2019
pubmed:
2
11
2019
medline:
20
2
2020
entrez:
2
11
2019
Statut:
ppublish
Résumé
Therapies targeting altered activity of pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) have been proposed for hepatomas. However, the activities of these pathways in hepatomas in vivo have not been distinguished. Here we examined pyruvate entry into the tricarboxylic acid (TCA) cycle through PDH versus PC in vivo using hepatoma-bearing rats. Hepatoma-bearing rats were generated by intrahepatic injection of H4IIE cells. Metabolism of In orthotopic hepatomas, pyruvate entry into the TCA cycle occurred exclusively through PDH and the excess PDH activity compared to normal liver was attributed to downregulated pyruvate dehydrogenase kinase (PDK) 2/4. However, pyruvate carboxylation via PC and gluconeogenesis were minimal, which was linked to downregulated forkhead box O1 (FoxO1) by Akt activity. In contrast to many studies of cancer metabolism, lactate production in hepatomas was not increased which corresponded to reduced expression of lactate dehydrogenase. The production of serine and glycine in hepatomas was enhanced, but glycine decarboxylase was downregulated. The combination of [U-
Sections du résumé
BACKGROUND
Therapies targeting altered activity of pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) have been proposed for hepatomas. However, the activities of these pathways in hepatomas in vivo have not been distinguished. Here we examined pyruvate entry into the tricarboxylic acid (TCA) cycle through PDH versus PC in vivo using hepatoma-bearing rats.
METHODS
Hepatoma-bearing rats were generated by intrahepatic injection of H4IIE cells. Metabolism of
RESULTS
In orthotopic hepatomas, pyruvate entry into the TCA cycle occurred exclusively through PDH and the excess PDH activity compared to normal liver was attributed to downregulated pyruvate dehydrogenase kinase (PDK) 2/4. However, pyruvate carboxylation via PC and gluconeogenesis were minimal, which was linked to downregulated forkhead box O1 (FoxO1) by Akt activity. In contrast to many studies of cancer metabolism, lactate production in hepatomas was not increased which corresponded to reduced expression of lactate dehydrogenase. The production of serine and glycine in hepatomas was enhanced, but glycine decarboxylase was downregulated.
CONCLUSIONS
The combination of [U-
Identifiants
pubmed: 31672442
pii: S0026-0495(19)30208-2
doi: 10.1016/j.metabol.2019.153993
pmc: PMC6892165
mid: NIHMS1542354
pii:
doi:
Substances chimiques
Pyruvate Dehydrogenase Complex
0
Glycerol
PDC6A3C0OX
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
153993Subventions
Organisme : NIDDK NIH HHS
ID : P01 DK058398
Pays : United States
Organisme : NIBIB NIH HHS
ID : P41 EB015908
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099289
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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