Mice without the ENT1 protein resist fatty liver disease

A liver with too much fat, a body that no longer responds well to insulin, and a disease that often gives no warning until scarring has set in: that is the everyday reality of the condition the researchers set out to understand. In a series of experiments, a team from the University of Barcelona found that mice without the ENT1 protein were markedly shielded from it. Their livers accumulated less fat, showed less inflammation and developed less fibrosis than those of ordinary mice.

ENT1 is a transporter, a protein that opens a gate in the membrane of liver cells and lets in small molecules called nucleosides. One of them, adenosine, plays a role in calming inflammation and in how cells cope with stress. When the researchers removed ENT1, the adenosine levels in the liver fell, and the animals were protected against the three hallmarks of the disease. The same mice also showed better glucose tolerance and greater insulin sensitivity, a sign that the effect may reach the whole body and not only the liver.

The story gets more complicated in human tissue. Analysing liver biopsies from patients and gene expression databases, the team found that ENT1 activity is higher in the early stages of the disease and decreases as it progresses, a pattern seen in both humans and mice. The authors suggest that in the early phase, more ENT1 could pull more adenosine into the liver, which would fit with how the disease starts and advances. In people with early-stage MASLD, higher liver ENT1 was linked to higher insulin levels and a higher HOMA-IR index, a standard measure of insulin resistance.

For patients, the immediate change is nothing: this is basic research, and the authors say ENT1's potential use in MASLD "still requires much more research, particularly in humans and with larger cohorts". What makes the finding worth watching is that the target is not new territory. Drugs able to inhibit ENT1 already exist, and some are in various phases of clinical development, which could shorten the path if the protein proves its value in people. The people who would benefit first would be those in the early stages of fatty liver disease, the window the data point to, but the sources give no timeline and no sign yet of when, or whether, a treatment could reach them.