Graphical abstract
Background and Aims: Development of efficient medications to treat non-alcoholic fatty liver disease (NAFLD) is urgently needed to control this prevalent disease. High fat diet (HFD) murine models are widely used in this area of research since they mimic the steatosis, inflammation and fibrosis typically shown in human NAFLD. We aim to identify a complete transcriptomic signature of this murine model and characterize the transcriptional impact exerted by different experimental anti-steatotic treatments.
Method: We carried out a systematic review in GEO database for transcriptomic studies comparing the hepatic gene expression of wild type HFD-fed C57BL6/J mice with that of control mice (normal diet, ND), and that of HFD-fed mice receiving potential anti-steatotic treatments. After performing a differential gene expression analysis, we conducted a meta-analysis to define the hepatic gene expression signature of HFD mice. We also evaluated the capacity of the anti-steatotic treatments to modulate this transcriptomic signature.
Results: In the systematic review, 21 selected studies were finally analysed, which included 24 different treatments. We obtained a transcriptomic signature of HFD murine models containing 2670 genes and, at the functional level, 2567 GO biological processes altered, most of them involved in immune response, cell death, response to stress, cell cycle and metabolism. Generally, treated HFD-mice showed a reversion of this HFD signature, although to different extent depending on the treatment. Among the genes of the HFD signature, we identified 325 genes whose expression was commonly reversed by treatments and 581 whose expression was not reversed. Regarding GO terms of the HFD signature, 1745 were reversed and 271 were not. The biological processes most frequently reversed were those related to lipid metabolism, cell death, cell proliferation, response to stress and immune system process. Conversely, processes related to nitrogen compound metabolism were usually not reversed. Comparing our HFD signature with a human NAFLD progression signature, we identified 62 common genes: 10 of them were of those generally reversed by treatments and 12 belong to the not reversed group.
Conclusion: This work defines a robust hepatic transcriptomic signature of the HFD-induced model of NAFLD and identifies a group of genes that are consistently modified by different experimental anti-steatotic treatments. These results may help to understand NAFLD transcriptional changes and contribute to the identification of new biomarkers and therapeutic targets for this pathology.
Keywords: steatosis, transcriptomic signature, MAFLD, therapeutic targets