University of Barcelona identifies ENT1 protein as potential treatment target for fatty liver disease

A University of Barcelona-led study published in Metabolism has identified the ENT1 nucleoside transporter protein as a potential therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD). Research in mice showed that ENT1 deficiency reduces liver adenosine, protecting against fat accumulation, inflammation, and fibrosis while improving insulin sensitivity. In humans, ENT1 expression rises in early MASLD stages, and existing ENT1 inhibitors offer potential future clinical treatments.

Study leadership and publication

• ▪The study was co-led by Sonia Fernández-Veledo alongside researchers from IRB CatSud, Universitat Rovira i Virgili, and CIBERDEM.
• ▪A University of Barcelona-led study published in Metabolism identified the ENT1 protein as a potential target for treating metabolic dysfunction-associated steatotic liver disease (MASLD).

Effects of ENT1 deficiency in mice

• ▪Mice deficient in ENT1 exhibited reduced liver adenosine levels and protection against inflammation, fibrosis, and excessive liver fat accumulation.
• ▪In animal models, ENT1 deficiency led to improved glucose tolerance and increased insulin sensitivity across overall body metabolism.

ENT1 expression in MASLD progression

• ▪Elevated liver ENT1 expression in patients with early-stage MASLD was associated with higher insulin levels and elevated HOMA-IR insulin resistance scores.
• ▪Hepatic ENT1 expression was higher during early stages of MASLD in both human biopsy data and mice, but decreased as the liver disease progressed.

Therapeutic potential of ENT1 inhibitors

• ▪Existing pharmacological drugs capable of inhibiting ENT1 activity are already undergoing various phases of clinical development.
• ▪Researchers emphasized that using ENT1 inhibitors for treating MASLD requires further evaluation in larger human clinical cohorts.

Role of ENT1 protein

• ▪The ENT1 protein acts as a transporter regulating the entry of small molecules known as nucleosides across liver cell plasma membranes.
• ▪The study identified the ENT1 protein as a regulator of systemic nucleoside metabolism and metabolic homeostasis.