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Researchers discover protein that protects against fatty liver, the most common liver disease in Western countries

The study, partly funded by Worldwide Cancer Research, reveals for the first time that the protein CPEB4 can prevent fatty liver disease. The results were published today in Nature Cell Biology.

A team co-led by two Worldwide Cancer Research scientists at the Institute for Research in Biomedicine (IRB Barcelona) and the IDIBAPS Biomedical Research Institute (part of the Hospital Clínic de Barcelona) has revealed the ability of the protein CPEB4 to prevent fatty liver disease. This condition generally leads to chronic inflammation (non-alcoholic steatohepatitis), which can trigger fibrosis, cirrhosis and ultimately liver cancer. This study, on the basic biology of the liver, paves the way to examine new therapeutic strategies to fight and prevent fatty liver disease. The results have appeared in Nature Cell Biology in the last 24 hours.

CPEB4 and fatty liver

The scientists depleted the levels of CPEB4 in mouse livers in order to study the role of this protein. They observed that the mice developed fatty liver as they aged. Furthermore, young CPEB4-depleted mice fed a high-fat diet also developed this condition.

The lead author, PhD student Carlos Maíllo, revealed that CPEB4 is essential to drive the liver’s response to stress. For example, under stress caused by the uncontrolled ingestion of fats, the endoplasmic reticulum—found inside the cell, which makes and folds proteins and is responsible for lipid metabolism (the break down and storage of fat)—stops its activity. This allows the cell to ‘clean-up’ the excess fat and this process is orchestrated by CPEB4.  The process varies in activity—being more active during the day (when the liver has most work) and dropping off at night.

Without CPEB4, the endoplasmic reticulum is unable to activate the stress response, thus causing hepatocytes to accumulate the lipids produced by the fatty liver.

New treatments?

Co-leader of the study, and Worldwide Cancer Research scientist, Dr Raúl Méndez, explains: “this new knowledge of CPEB4’s role in the liver could be particularly useful for people with variations of the protein.  It could act as a predictive marker – to pre-empt who might be at a higher risk of developing fatty liver.  The knowledge could also then serve to help prevent fatty liver, for example, through improvements in a person’s diet and better choice of eating times.

The researchers managed to reverse fatty liver disease in mice by treatment with a drug called Tudca, which treats other liver disorders. The drug exerted the same effect on the proteins that CPEB4 activates. “Our findings could contribute to the development of new treatments.  In the future it may be possible to design molecules like Tudca that specifically target CPEB4, thus enhancing the liver clean-up process,” proposes Dr Méndez.

This lab-based discovery research study does not have a direct and immediate clinical application, but it lays down the foundation for the applied science that follows,” says Dr Mercedes Fernández, co-leader of the study and Worldwide Cancer Research scientist. Dr Fernández warns, “Given the obesity epidemic in the US and Western world, an increase in those affected by non-alcoholic fatty liver disease is expected in the coming decades and we still do not have a suitable treatment for this condition.  A fundamental understanding of this medical problem is therefore essential for development of novel treatment strategies.”

Dr Lynn Turner, Head of Research at Worldwide Cancer Research said: “This research just goes to demonstrate the importance of funding early stage research. The team in Barcelona are paving the way for future treatments and using their research to address one of the symptoms of a growing problem.”

It is estimated that between 80 and 100 million people in the US alone suffer from fatty liver disease. People with this disease have an increased risk of cirrhosis and liver cancer. Moreover, liver cancer incidence has more than tripled since 1980 and is the primary cause of death in patients with cirrhosis.

Read more about the grant we gave to Dr Mendez and the team here.

The work was supported by a grant from Worldwide Cancer Research. The research was also supported by the Spanish Association Against Cancer (AECC), the Fundación Botín by Banco Santander through its Santander Universities Global Division, the Spanish Ministry of Economy and Competitiveness/ERDF and the Government of Catalonia.

Reference article: Circadian- and UPR-dependent control of CPEB4 mediates a translational response to counteract hepatic steatosis under ER stress

Nature Cell Biology (2017) DOI: 10.1038/ncb3461