Phospholipid isotope tracing suggests ß-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma.
Biochim Biophys Acta Mol Cell Biol Lipids
; 1869(6): 159514, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-38795827
ABSTRACT
Activating mutations in the CTNNB1 gene encoding ß-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). Profound alterations in lipid metabolism, including increases in fatty acid oxidation and transformation of the phospholipidome, occur in HCC with CTNNB1 mutations, but it is unclear what mechanisms give rise to these changes. We employed untargeted lipidomics and targeted isotope tracing to measure phospholipid synthesis activity in an inducible human liver cell line expressing mutant ß-catenin, as well as in transgenic zebrafish with activated ß-catenin-driven HCC. In both models, activated ß-catenin expression was associated with large changes in the lipidome including conserved increases in acylcarnitines and ceramides and decreases in triglycerides. Lipid isotope tracing analysis in human cells revealed a reduction in phosphatidylcholine (PC) production rates as assayed by choline incorporation. We developed lipid isotope tracing analysis for zebrafish tumors and observed reductions in phosphatidylcholine synthesis by both the CDP-choline and PEMT pathways. The observed changes in the ß-catenin-driven HCC phospholipidome suggest that zebrafish can recapitulate conserved features of HCC lipid metabolism and may serve as a model for identifying future HCC-specific lipid metabolic targets.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
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Tipos_de_cancer
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Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Fosfatidilcolinas
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Peixe-Zebra
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Carcinoma Hepatocelular
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Beta Catenina
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Neoplasias Hepáticas
Limite:
Animals
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Humans
Idioma:
En
Revista:
Biochim Biophys Acta Mol Cell Biol Lipids
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos