Grant: Project Grant

Non-alcoholic fatty liver disease (NAFLD) is an obesity-linked metabolic disorder that affects >25% of adults in Canada. Most people with NAFLD have a benign case of simple steatosis (excess fat storage in liver) but an estimated 1 million Canadians will progress to a more severe pathology called non-alcoholic steatohepatitis (NASH), which is characterized by steatosis, inflammation, and fibrosis of the liver. NASH is the leading cause of liver failure and liver cancer and also contributes to cardiovascular complications such as heart failure and stroke. In obesity, a key determinant underlying NASH and its detrimental impact on health is the capacity of the liver to resist the metabolic stress imposed by excess levels of cholesterol and its metabolic product bile, which promote liver cell damage and inflammation. Hence, there is an important role for therapeutics that are specifically designed to enhance the capacity of liver to manage elevated metabolism of cholesterol and bile. In our proposed research, we will investigate the mechanisms by which a pair of evolutionarily conserved stress-adaptive transcription factors named NRF1 & NRF2 regulate metabolic, stress, and inflammatory processes to promote resistance to the stress of elevated cholesterol and bile in liver during obesity. Our goal is to determine whether NRF1 & NRF2 work independently or in a coordinated manner to engage adaptive countermeasures and whether these actions are capable of resolving liver cell damage and inflammation caused by excess cholesterol & bile. We will also test whether stimulating these transcription factors may be an effective strategy to treat NASH in obesity. We anticipate these findings will be relevant for the large & growing population of Canadians with obesity who are at risk for NASH and its consequential impact on liver failure, liver cancer, heart failure and stroke.