Simultaneous Activation of Beta-Oxidation and De Novo Lipogenesis in MASLD-HCC: A New Paradigm

Overview

Journal Liver Int

Date 2025 Jan 22

PMID 39840890

Authors

Fatima Dahboul

Jihan Sun

Benjamin Buchard

Natali Abeywickrama-Samarakoon

Estelle Pujos-Guillot

Stephanie Durand

Melanie Petera

Delphine Centeno

Francesca Guerrieri

Massimiliano Cocca

Massimo Levrero

Adrien Rossary

Delphine Weil

Vincent Di Martino

Aicha Demidem

Armando Abergel

Affiliations

Soon will be listed here.

Abstract

Background And Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of hepatocellular carcinoma (HCC). In this study, we combine metabolomic and gene expression analysis to compare HCC tissues with non-tumoural tissues (NTT).

Methods: A non-targeted metabolomic strategy LC-MS was applied to 52 pairs of human MASLD-HCC and NTT separated into 2 groups according to fibrosis severity F0F1-F2 versus F3F4. The expression of genes related to de Novo lipogenesis (DNL) and fatty acid oxidation (FAO) has been analysed by quantitative RT-PCR and/or interrogation of RNA-seq datasets in 259 pairs of tissues (MASLD-HCC vs. VIRUS-HCC).

Results: Metabolomic analysis revealed that acylcarnitines were the main discriminating metabolites according to fibrosis severity when we compared MASLD-HCC-F0F1-F2 versus NTT and MASLD-HCC-F3F4 versus NTT. Based on these metabolomic data, the analysis of a panel of 15 selected genes related to DNL and FAO indicated that there is no difference between the 2 groups of MASLD-HCC. In contrast the same comparative gene analysis according to the aetiology of HCC: MASLD-HCC versus VIRUS-HCC showed that both aetiologies shared the same upregulation of genes involved in DNL. However, five genes involved in FAO (HADHA, CRAT, CPT1, CPT2 and PPARA) are upregulated exclusively in MASLD-HCC. This result indicates that FAO and DNL pathways are simultaneously activated in MASLD-HCC in contrast to VIRUS-HCC.

Conclusions: These results suggest that, the involvement of adaptive metabolic pathways is different depending on the aetiology of HCC. Moreover, the dogma that simultaneous activation of FAO and DNL is incompatible in cancer would not apply to MASLD-HCC.

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