How the liver transcriptome and lipid composition influence the progression of nonalcoholic fatty liver disease to hepatocellular carcinoma in a murine model

Marvin Leopold; Paola Berenice Mass-Sanchez; Marinela Krizanac; Paula Štancl; Rosa Karlić; Patricia Prabutzki; Victoria Parafianczuk; Jürgen Schiller; Anastasia Asimakopoulos; Kathrin M Engel; Ralf Weiskirchen

doi:10.1016/j.bbalip.2024.159574

How the liver transcriptome and lipid composition influence the progression of nonalcoholic fatty liver disease to hepatocellular carcinoma in a murine model

Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jan;1870(1):159574. doi: 10.1016/j.bbalip.2024.159574. Epub 2024 Nov 5.

Affiliations

¹ Institute for Medical Physics and Biophysics, Leipzig University, Faculty of Medicine, 04107 Leipzig, Germany; Klinik für Neurologie, Sana Klinikum Borna, 04552 Borna, Germany. Electronic address: [email protected].
² Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, 52074 Aachen, Germany. Electronic address: [email protected].
³ Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, 52074 Aachen, Germany. Electronic address: [email protected].
⁴ Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia. Electronic address: [email protected].
⁵ Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia. Electronic address: [email protected].
⁶ Institute for Medical Physics and Biophysics, Leipzig University, Faculty of Medicine, 04107 Leipzig, Germany. Electronic address: [email protected].
⁷ Institute for Medical Physics and Biophysics, Leipzig University, Faculty of Medicine, 04107 Leipzig, Germany.
⁸ Institute for Medical Physics and Biophysics, Leipzig University, Faculty of Medicine, 04107 Leipzig, Germany. Electronic address: [email protected].
⁹ Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, 52074 Aachen, Germany.
¹⁰ Institute for Medical Physics and Biophysics, Leipzig University, Faculty of Medicine, 04107 Leipzig, Germany. Electronic address: [email protected].
¹¹ Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, 52074 Aachen, Germany. Electronic address: [email protected].

PMID: 39510374
DOI: 10.1016/j.bbalip.2024.159574

Abstract

The incidence of nonalcoholic fatty liver disease (NAFLD) has been steadily increasing in Western society in recent years and has been recognized as a risk factor for the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the progression from NAFLD to HCC are still unclear, despite the use of suitable mouse models. To identify the transcriptional and lipid profiles of livers from mice with NAFLD-HCC, we induced both NAFLD and NAFLD-HCC pathologies in C57BL/6J mice and performed RNA-sequencing (RNA-seq) and targeted lipidomic analysis. Our RNA-seq analysis revealed that the transcriptional signature of NAFLD in mice is characterized by changes in inflammatory response and fatty acid metabolism. Moreover, the signature of NAFLD-HCC is characterized by processes typically observed in cancer, such as epithelial to mesenchymal transition, angiogenesis and inflammatory responses. Furthermore, we found that the diet used in this study inhibited cholesterol synthesis in both models. The analysis of lipid composition also showed a significant impact of the provided diet. Therefore, our study supports the idea that a Western diet (WD) affects metabolic processes and hepatic lipid composition. Additionally, the combination of a WD with the administration of a carcinogen drives the progression from NAFLD to HCC.

Keywords: Fatty acid metabolism; Hepatocellular carcinoma; Lipidomics; Nonalcoholic fatty liver disease.

MeSH terms

Animals
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / metabolism
Carcinoma, Hepatocellular* / pathology
Diet, Western / adverse effects
Disease Models, Animal*
Disease Progression*
Lipid Metabolism* / genetics
Liver Neoplasms* / genetics
Liver Neoplasms* / metabolism
Liver Neoplasms* / pathology
Liver* / metabolism
Liver* / pathology
Male
Mice
Mice, Inbred C57BL*
Non-alcoholic Fatty Liver Disease* / genetics
Non-alcoholic Fatty Liver Disease* / metabolism
Non-alcoholic Fatty Liver Disease* / pathology
Transcriptome*