Transcription factor interplay as a driving force in the hepatic response to fasting and its dysregulation in metabolic disease

Metabolic diseases, including diabetes, obesity, and non-alcoholic fatty liver disease are reaching epidemic levels worldwide. Improper cellular energy production, storage, and use underlie many of these conditions. The enzymes that control glucose, fat, and ketone body production in the liver are under the control of numerous proteins called transcription factors. In response to fasting, a specific series of transcription factors are required to ensure proper activation of the enzymes that are important for maintaining fuel levels in the absence of an external food source.

In this project, researchers will use specific gene knockout mouse models of these transcription factors, in combination with state-of-the-art DNA and RNA sequencing technologies, to uncover the importance of these transcription factors in modifying the basic physiologic response to fasting and how these are modified in disease. The team will also test novel small molecules that target these transcription factors for their ability to restore the proper fasting response in a mouse model of diet-induced obesity.

The project was selected for funding through the fifth research competition of the Joint Canada-Israel Health Research Program. This initiative is a partnership between IDRC, the Canadian Institutes of Health Research, the Israel Science Foundation, and the Azrieli Foundation.