An international study led by the Lipids&Liver research team at the UPV/EHU-University of the Basque Country, the results of which have recently been published in the prestigious journal Cancer Research, has demonstrated that inhibiting either of the proteins E2F1 or E2F2 in the liver protects against the development of obesity-driven nonalcoholic fatty liver disease and its progression to cancer. These two proteins are therefore powerful therapeutic targets for treating this disease.
Over the last decade, nonalcoholic fatty liver disease, or metabolic hepatic steatosis, which affects approximately 80% of obese patients, has emerged as an important risk factor for cancer, including hepatocellular carcinoma (the most common primary liver cancer in the world). There is no specific pharmacological treatment for nonalcoholic fatty liver disease, and the therapeutic options for hepatocellular carcinoma are still very limited. Moreover, nonalcoholic fatty liver disease-driven hepatocellular carcinoma has been associated with shorter survival time and a more advanced tumour stage.
The Lipids&Liver research team at the UPV/EHU-University of the Basque Country, which has extensive experience studying metabolic alterations associated with liver disease, has identified two new proteins, transcription factors E2F1 and E2F2, that are key contributors to the development of obesity-driven nonalcoholic fatty liver disease and its progression to hepatocellular carcinoma. The study, led by Dr Patricia Aspichueta, with Francisco Gonzalez-Romero and Daniela Mestre (also from the Lipids&Liver team) as first signatories, has been published in the prestigious high-impact journal Cancer Research.
The study found that E2F1 and E2F2 levels were higher in the livers of obese patients with nonalcoholic fatty liver disease or hepatocellular carcinoma than in healthy livers, and that these factors exert some degree of control over the metabolism. By using animal models supported by cell models, the study demonstrates that 'the absence of E2F1 or E2F2 results in (almost total) resistance to the development of nonalcoholic fatty liver disease associated with a high-fat diet and its progression to hepatocellular carcinoma', explains Dr Aspichueta.
This finding is extremely important because there is, as yet, no specific, effective treatment for either nonalcoholic fatty liver disease or hepatocellular carcinoma."
Dr Patricia Aspichueta
Moreover, the prevalence of nonalcoholic fatty liver disease, which is a risk factor for the development of hepatocellular carcinoma, 'is increasing, since between 70% and 80% of obese patients suffer from this disease', she explains.
Altered lipid metabolism
In the study, which was conducted in collaboration with researchers from other Spanish and international groups, 'we have identified the proteins E2F1 and E2F2, traditionally known as cell proliferation activators, as key regulators of lipid consumption in the liver. This means that, when an animal or a cell model is genetically modified to eliminate either of these two proteins, hepatic fatty acids are rapidly consumed by mitochondrial lipid oxidation', explains Dr Aspichueta.
In the case of obese patients with nonalcoholic fatty liver disease or patients with nonalcoholic fatty liver disease-driven hepatocellular carcinoma, an increase in E2F1 and/or E2F2 creates resistance to the consumption of fatty acids, which are stored in lipid droplets, thereby generating new metabolic alterations. 'The mechanism by which the E2F1 and E2F2 factors regulate the consumption of lipids in the liver involves the CPT2 protein, which is one of those responsible for channelling fatty acids towards the mitochondrion for consumption. Consequently, high levels of E2F1 and E2F2 repress CPT2, preventing lipids from passing into the mitochondrion and inducing their storage alongside other pro-carcinogenic metabolites (acylcarnitines)', explains the doctor. This discovery identifies 'E2F1 and E2F2 as potential therapeutic targets for preventing the progression of nonalcoholic fatty liver disease and the development of hepatocellular carcinoma', she concludes.
The study was led by Dr Patricia Aspichueta, lead researcher with the Lipids&Liver group at the Department of Physiology, within the Faculty of Medicine and Nursing, in collaboration with other groups from the UPV/EHU-University of the Basque Country, ISS Biocruces, CIC bioGUNE, ISS Biodonostia, the Marqués de Valdecilla University Hospital (Cantabria), the University of Copenhagen (Denmark), Ionis Pharmaceuticals (Carlsbad, California), CIBERehd, CIBERDEM and CIBERER.
González-Romero, F., et al. (2021) E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment. Cancer Research. doi.org/10.1158/0008-5472.CAN-20-2052.