The mechanisms that cause the world's most common chronic liver disease - Metabolic dysfunction-associated steatotic liver disease (MASLD) - to develop and progress are not still fully understood. Now, a study by the University of Barcelona has identified a new factor involved in the development of the disease: the protein ENT1, which allows the transport of small molecules essential for the functioning of liver cells into the cell. The results of the study, carried out with patients and animal models, open the door to exploring future therapies.
The research, published in the journal Metabolism, is led by Professor Sandra Pérez-Torras, member of the Department of Biochemistry and Molecular Biomedicine at the UB's Faculty of Biology, the Institute of Biomedicine of the University of Barcelona (IBUB) and the Sant Joan de Déu Research Institute (IRSJD). Other participants in the study are Professor Marçal Pastor-Anglada, Aida Mata-Ventosa, one of the article's first authors, and Maria Isabel Hernández-Alvarez, all three researchers at the IBUB and the IRSJD.
Sonia Fernández-Veledo, from the Institut d'Investigació Sanitària Pere Virgili (IISPV), the Universitat Rovira i Virgili and the CIBER Area for Diabetes and Associated Metabolic Diseases (CIBERDEM), also co-leads the study carried out together with experts from other national and international institutions.
Protection against fat, inflammation and fibrosis
This chronic disease, which is not caused by alcohol consumption but by metabolic disturbances such as obesity, is characterized by the excessive accumulation of fat in the liver and can progress to more severe forms, such as advanced fibrosis or liver cancer.
To uncover the liver mechanisms that contribute to the early stages of the disease, the researchers focused on ENT1, a transporter protein that regulates the entry of small molecules called nucleosides across the plasma membrane. Thus, the team studied the expression of ENT1 - that is, the extent to which the gene responsible for producing this transporter is active - and its impact on liver and whole-body metabolism.
Experiments in mice with and without ENT1 have established a link between this transporter, nucleoside levels - particularly adenosine, a nucleoside involved in regulating inflammation and in cells' response to stress - and the development of the characteristic alterations associated with the disease.
The results show that ENT1 deficiency reduces adenosine levels in the liver and protects animals against inflammation, fibrosis and excessive fat accumulation in this organ. Moreover, mice lacking ENT1 show improved glucose tolerance and increased insulin sensitivity, suggesting that the transporter's effects may extend beyond the liver and affect the organism's overall metabolism.
