Northwestern scientists have identified a new function for a transcription factor called BCL6, finding that it switches off genes involved in lipid metabolism. According to the study published in eLife, little is known about metabolic switches like BCL6, and understanding their function may point to new ways to treat obesity and its various health consequences.
Grant Barish, MD, assistant professor of Medicine in the Division of Endocrinology, Metabolism and Molecular Medicine, was senior author of the study, and Meredith Sommars, sixth-year student in the Driskill Graduate Program in Life Sciences (DGP), was lead author of the study.
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, which can lead to fatty liver disease or even liver cancer. According to the authors, it is important to fully understand the mechanisms that lead to fat accumulation in the liver in order to develop new treatments.
The human body is designed to even out the highs and lows of an unpredictable diet by storing and releasing calories. When people are well-fed, liver cells switch on genes involved in making fat. When they have not eaten for a while, liver cells switch them off and turn on other genes involved in metabolizing lipids, or burning fat cells. 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, scientists know much less about the repressors that stop cells burning fat when there is plenty of nutrition available. To find out more, Northwestern investigators studied the repressor BCL6 in mouse liver cells.
Through genome-wide DNA binding and transcriptome analyses, Barish and his colleagues discovered that BCL6 interacts with hundreds of the same genes as PPAR alpha.
“The convergence between BCL6 and PPARa on thousands of neighboring DNA sites in the liver was not expected, but this genomic overlap pointed us to a function for BCL6 in lipid metabolism,” Barish said.
When the mice were eating, BCL6 turned 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 stores in their livers.
This makes BCL6 inhibition an interesting target for boosting the liver’s ability to burn excess fat, according to the authors, and future study will aim to better characterize the exact mechanisms by which the fat-burning operates.
“Our genetic findings predict that they have potential in the treatment of fatty liver disease,” Barish said. “Several such compounds are under development by pharmaceutical companies.”
Other Northwestern co-authors include Barish laboratory members Krithika Ramachandran, sixth-year student in the DGP; Madhavi Senagolage, a seventh-year student in the DGP; Derrik Germain, a former student in the DGP; Christopher Futtner, research associate; and Amanda Allred and Yasuhiro Omura, research technologists.
This work was funded by National Institutes of Health (NIH) grants R01DK108987, K08HL092298 and T32 GM00, and American Diabetes Association Award 1–17-IBS-137.
