A new mechanism explains how protein production is regulated in fatty liver under metabolic stress

Fatty liver is an increasingly common disease that can progress toward more severe forms, involving inflammation, fibrosis, and, in some cases, cirrhosis and liver cancer. While it is known that a high-fat diet alters gene activity, it was not yet well understood how these changes affect cellular function.

Now, a study led by Drs. Raúl Méndez and Patrick Aloy at IRB Barcelona, and Dr. Mercedes Fernández at Clinic-IDIBAPS, reveals that a large part of this response occurs at a level different from what had been studied to date. The work—with Dr. Eulalia Belloc, Dr. Vittorio Calderone, and Dr. Salvador Naranjo as lead authors—shows that this control is exerted over how genetic messages are used to produce proteins.

In cells, information from DNA is copied into RNA, which acts as an intermediary to manufacture proteins, which are responsible for cellular function.

“Until now, we had focused on how RNA levels change, but that does not always translate into changes in the proteins they encode. This study shows that regulation in the step from RNA to protein affects 70% of the genes involved in the cellular response to excess fat,” explains Dr. Raúl Méndez, ICREA researcher and head of the Translational Control of Cell Cycle and Differentiation laboratory at IRB Barcelona.

New tools for understanding cellular regulation

To reach this conclusion, the team combined experimental approaches in animal models of metabolic stress with patient data and computational analyses, intersecting different -omics approaches. This methodology allowed them to map, for the first time, the mismatch between genetic messages (RNA) and their final product (proteins).

“Thanks to an integrated multi-omic analysis, we have discovered that the genetic map we were using to understand fatty liver was incomplete. We can now see which signals are truly important and which do not have a direct impact, forcing us to reinterpret many studies based solely on RNA levels,” explains Dr. Patrick Aloy, ICREA researcher and head of the Structural Bioinformatics and Network Biology laboratory at IRB Barcelona.

CPEB4: a regulator of the stress response

Unlike other tissues, the liver cannot eliminate damaged cells; instead, it must adapt to continue functioning, which requires precise control of protein production. To understand what controls these processes, the team studied the role of CPEB4, a protein that regulates RNA translation under conditions of chronic stress.

The study shows that CPEB4 acts as a central regulator that tunes which messages are translated at any given moment, allowing cells to adjust their function in adverse conditions. Beyond its function, the work identifies the molecular mechanism that explains how the translation of these messages is selectively regulated.

“The most important thing we see is that these messages simultaneously contain signals that favour or limit their translation, and it is the balance between the two that allows their activity to be regulated. This is the role played by CPEB4,” explains Dr. Méndez.

A new perspective on the disease

These mechanisms not only allow cells to adapt to stress but are also related to the progression of fatty liver toward more severe forms, such as inflammation, fibrosis, or liver cancer.

“The liver must continue to function even under conditions of chronic stress, which requires activating extremely precise adaptation mechanisms. Understanding these processes is fundamental to explaining how the disease advances toward more severe forms and opens the door to identifying new therapeutic targets to halt this deterioration,” concludes Dr. Mercedes Fernández, researcher and head of the IDIBAPS research group Translational Control in Liver Disease and Cancer.

The project was started thanks to funding from the ”la Caixa” Foundation and was developed and completed with the support of the AECC, within the framework of a multidisciplinary collaboration spanning more than ten years. The work has also received funding from the Marató de TV3, the BBVA Foundation, Worldwide Cancer Research, the Spanish Ministry of Science, Innovation and Universities, and the Generalitat de Catalunya, as well as the Carlos III Health Institute and the European Commission.
 

Related article:
Posttranscriptional control of MASLD through ER stress adaptation
Eulalia Bellocº, Vittorio Calderoneº, Salvador Naranjo-Suarezº, Lidia Mateo, Judit Martin, Florencia Malizia, Annarita Sibilio, Veronica Chanes, Marta Ramirez-Pedraza, M. Eugenia Delgado, Uta Drebber, Karl-Peter Rheinwalt, Sabine Klein, Maximilian Joseph Brol, Robert Schierwagen, Jonel Trebicka, Patrick Aloy*, Mercedes Fernandez* & Raul Mendez*
Science Advances (2026) DOI: 10.1126/sciadv.aea4125