Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis

Obesity has nearly tripled worldwide since the 1970s. A major health concern related to obesity is that excess fat can spill into organs such as the liver. This can lead to fatty liver disease or even liver cancer. Therefore, it is important to fully understand the mechanisms that lead to fat accumulation in the liver in order to develop new treatments. Our bodies are designed to even out the highs and lows of an unpredictable diet by storing and releasing calories. When we are well-fed, liver cells switch on genes involved in making fat. When we have not eaten for a while, they switch them off and turn on genes involved in burning fat. Each switch involves thousands of genes, controlled by proteins called transcription factors. Some work as activators, turning genes on, whilst others work as repressors, turning genes off. For example, the transcription factor PPAR alpha is a well-known activator that helps to regulate fat burning. However, we know much less about the repressors that stop cells burning fat when there is plenty of food available. To find out more, Sommars et al. studied the repressor BCL6 in mouse liver cells. The results revealed that BCL6 interacts with hundreds of the same genes as PPAR alpha. When the mice were eating, BCL6 turns off the genes involved in fat burning, but when they were starved PPAR alpha activated those genes. However, when BCL6 was experimentally removed, many fat-burning genes were permanently switched on. So, even when mice were fed a high-fat diet, they burned off fat in their livers. Understanding the role of genetic switches like PPAR alpha and BCL6 is crucial for understanding how and why our bodies store energy. This could help us to create treatments that enhance the liver's ability to burn excess fat.