Metabolic Liver Disease Affects 1.3 Billion People Globally
Metabolic dysfunction-associated steatotic liver disease affects approximately 1.3 billion people worldwide, representing 16% of the global population, according to the Global Burden of Disease Study 2023. Commonly known as fatty liver disease, it stands as the most frequent chronic liver ailment on a global scale. The condition stems from metabolic alterations such as obesity rather than alcohol consumption, and it involves an excessive buildup of fat in the organ that can progress to advanced fibrosis or liver cancer.
While the condition’s vast scale is clear, the biological mechanisms driving its onset and progression have remained poorly understood. Researchers at the University of Barcelona have now identified a key biological component: the ENT1 protein. This transporter regulates the entry of small molecules essential for liver cell function, playing a decisive role in how the pathology begins and advances.
The study, published in the journal Metabolism, was led by Sandra Pérez-Torras of the Department of Biochemistry and Molecular Biomedicine at the Faculty of Biology of the University of Barcelona, alongside the Institute of Biomedicine of the University of Barcelona and the Sant Joan de Déu Research Institute. Scientists conducted the work using both animal models and human patient biopsies, allowing them to compare results across two different planes to strengthen their conclusions.
To examine early-stage liver changes, the team focused on ENT1 and adenosine, a nucleoside that acts both as a building block for genetic material and as a biological signal. Concentrations of adenosine inside and outside cells directly influence how liver tissue responds to damage, accumulates fat, and regulates inflammation. Experiments showed that mice lacking the ENT1 transporter had reduced liver adenosine levels alongside notable protection against inflammation, fibrosis, and excessive fat accumulation, as communicated by the University of Barcelona. These mice also displayed improved glucose tolerance and greater insulin sensitivity.
Parallel research offers additional insight into why certain fatty livers progress to severe injury while others do not. Researchers at the University of Utah identified a separate protein, EFHD1, that appears to drive the transition from simple fat accumulation to inflammation and scarring by triggering an abnormal antiviral immune response. Published in the Journal of Clinical Investigation, the study found that elevated lipid levels in mice fed high-fat and high-sugar diets increased EFHD1 expression, causing mitochondria to divide excessively and release double-stranded RNA into the cell.
This release tricks the cell into activating an antiviral defense pathway as if it were infected by a virus like hepatitis C. When the researchers blocked or reduced EFHD1 levels in diet-induced and drug-induced liver damage models, indicators of inflammation and liver scarring decreased by 30% to 60%. Study author David Eberhardt, an internal medicine doctor and postdoctoral researcher at University of Utah Health, noted that targeting these underlying pathways limits damage caused by fat accumulation, giving individuals more time to make lifestyle changes.
Liver Protein Links to Insulin Resistance in Early Disease
Human biopsy data from the University of Barcelona research further connected ENT1 levels to systemic metabolic health. In patients with early-stage disease, higher liver presence of ENT1 associated with elevated blood insulin levels and a higher HOMA-IR index, a clinical indicator measuring cellular resistance to insulin. Although medications capable of inhibiting ENT1 exist and are in various phases of clinical development for other conditions, the Spanish research team remains cautious, stating that potential therapeutic use for metabolic liver disease requires much larger human cohort studies.
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