Researchers at the Institute for Research in Biomedicine (IRB Barcelona), have discovered that the CPEB4 protein is able to prevent the over-accumulation of fat in liver cells, known as hepatocytes. The study – which was published in the journal, Nature Cell Biology – could aid in the development of new therapeutics for non-alcoholic fatty liver disease (NAFLD).
Obesity and lifestyle factors are thought to contribute most to the development of NAFLD. If left unchecked, it often develops into non-alcoholic steatohepatitis (NASH), which can contribute to cirrhosis and cancer of the liver.
Interestingly, genomics studies have found that variants of the CPEB4 gene have been associated with impaired fat metabolism, potentially contributing to the accumulation of fat in the liver. In order to further study this link, the IRB Barcelona researchers engineered CPEB4-knockout mice, lacking protein expression in their liver cells.
The researchers found that the mice accumulated excess fat in their liver tissue over time. When CPEB4-knockout mice were fed a high-fat diet from a young age, they developed fatty liver more quickly.
In characterizing the molecular function of the CPEB4 protein, they found that it is an essential component in the liver’s response to stress. Over-consumption of fatty foods can trigger this stress response, wherein CPEB4 targets the endoplasmic reticulum – an organelle involved in cellular lipid metabolism – to induce a “clean up” mechanism.
In humans, CPEB4 is most active during the day – when the largest consumption of food occurs – and less active at night. When CPEB4 expression is depleted in knockout mice, the endoplasmic reticulum is unable to initiate the stress response, leading to accumulation of lipids in hepatocytes.
“Knowledge of the hepatic function of CPEB4 could be useful as a predictive marker for those people with variants of this protein, thus serving to prevent this condition, for example, through improvements in diet and better choice of eating times,” said Raúl Méndez, researcher at IRB Barcelona and senior study author. “Such knowledge could also contribute to the development of treatments that boost the clean-up process.”
In testing a drug known as tauroursodeoxy-cholic acid (TUDCA), the researchers found they could reverse NAFLD in mice. This bile salt acts as a replacement for the missing CPEB4 protein, and activates the lipid cleanup mechanism in the liver cells.
“This basic research study does not have a direct and immediate clinical application, but it lays down the foundation for the applied science that follows,” said Mercedes Fernández, co-leader of the study and head of the group at the Biomedical Research Networking Center of Hepatic and Digestive Diseases (CIBEREHD). “Given the obesity epidemic in the US and worldwide, 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.”