The team - led by researchers from the Institute for Research in Biomedicine (IRB Barcelona) and the IDIBAPS Biomedical Research Institute, which is part of the Hospital Clínic de Barcelona - reports the findings in the journal Nature Cell Biology.

The researchers hope that the discovery will lead to treatments that fight and even prevent fatty liver - also known as nonalcoholic fatty liver disease - which is the most common chronic liver disease in developed countries.

Dr. Mercedes Fernández, one of the study co-leaders and head of the IDIBAPS group, says that while their study "does not have a direct and immediate clinical application," it does, however, lay down "the foundation for the applied science that follows."

Nonalcoholic fatty liver disease (NAFLD) is a condition in which too much fat builds up in hepatocytes, the most common cell in the liver. It is similar to alcoholic liver disease, except that it is also found in people who drink little or no alcohol.

NAFLD can progress to nonalcoholic steatohepatitis (NASH) where, in addition to fat deposits, the liver also shows signs of inflammation and cell damage. NASH can also lead to fibrosis, cirrhosis, and eventually liver cancer.
 

CPEB4 depletion led to fatty liver in mice

Nobody knows exactly what causes fatty liver, although we do know that it tends to develop in people who are obese or overweight, or those who have diabetes, high cholesterol, or high triglycerides. It can also result from rapid weight loss and poor eating habits.

However, some people without these risk factors also develop NAFLD. Estimates suggest that up to 25 percent of people in the United States have NAFLD.

Dr. Fernández and colleagues note that some large genomics studies have linked variants of the gene that codes for the CPEB4 protein with disruption of fat metabolism.

For their investigation, they studied mice with low expression of CPEB4 gene in their livers.

They found that the mice developed fatty liver as they aged. They also found that feeding young CPEB4-depleted mice a high-fat diet led them to develop a more pronounced form of fatty liver disease.

Further investigation into how CPEB4 behaves at the molecular level suggests that the protein plays a key role in the liver's stress response.

Putting liver cells under stress - as a result of a high-fat diet, for example - upsets the equilibrium in a cell component called the endoplasmic reticulum (ER).
 

Without CPEB4, the ER responds ineffectively to stress

The ER carries out many tasks, including making proteins and lipids, as well as clearing away accumulated excess.

The researchers found that the ER adapts to stress by releasing CPEB4 to restore equilibrium - for instance, by boosting the clean-up of accumulated excess.

They also found that circadian rhythm influences the release of CPEB4; it is more active during the day (when the liver has the most work to do) and least active at night.

The team suggests that without CPEB4, the ER cannot properly restore equilibrium in response to stress, which results in the buildup of lipids and leads to fatty liver.

In a final set of experiments, the researchers showed that a drug called Tudca, currently used to treat other liver complaints, reversed fatty liver in the mice. The drug appears to trigger the same cleanup function as the proteins (called chaperones) that are activated by CPEB4.

The researchers suggest that their findings could lead to studies that show people with certain variants of CPEB4 are more susceptible to fatty liver. These people can then be advised to improve their diets or change their eating times.

The discovery could also lead to new treatments that target CPEB4 to boost the cleanup process in the ER.

    "Given the obesity epidemic in the U.S. and worldwide, an increase in those affected by nonalcoholic 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. Mercedes Fernández