Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition globally, yet its developmental mechanisms are not fully understood. A new study, published in the journal Metabolism, has identified the ENT1 protein as a novel determinant in the progression of this disease. This transporter protein regulates the entry of small molecules essential for the function of liver cells.
The research, led by Professor Sandra Pérez-Torras from the University of Barcelona (UB), the Biomedicine Institute (IBUB), and the Sant Joan de Déu Research Institute (IRSJD), with significant contributions from Professor Marçal Pastor-Anglada, postdoctoral researcher Aida Mata-Ventosa, and Maria Isabel Hernández-Alvarez, also from UB, IBUB, and IRSJD, involved Sonia Fernández-Veledo from IRB CatSud, the Universitat Rovira i Virgili, and CIBERDEM. The study was conducted using animal models and patient data, with the collaboration of national and international experts.
MASLD, which is not caused by alcohol but by metabolic alterations such as obesity, is characterized by excessive fat accumulation in the liver and can progress to severe forms like advanced fibrosis or liver cancer. Experiments with mice have shown that ENT1 deficiency reduces adenosine levels in the liver, offering protection against inflammation, fibrosis, and excessive fat accumulation. Furthermore, mice lacking ENT1 exhibit better glucose tolerance and increased insulin sensitivity, suggesting a systemic impact of the transporter.
Analysis of liver biopsies from patients and gene expression databases indicates that ENT1 expression varies with the stage of MASLD. It is higher in the initial phases but decreases as the disease progresses, suggesting ENT1's role in transporting adenosine during the early stages. In patients with early MASLD, higher ENT1 expression is associated with elevated insulin levels and insulin resistance.
The researchers conclude that ENT1 acts as a regulator of systemic nucleoside metabolism and metabolic homeostasis, highlighting nucleoside transport as a previously undervalued axis in MASLD development. These findings position ENT1 as a potential therapeutic target, as drugs capable of inhibiting its activity already exist and some are in various stages of clinical development.
