Grant: CIHR Fellowship

More than 1.9 billion people worldwide suffer from obesity, which is associated with accumulation of fat in the liver known as steatosis. It is estimated that 35% of people with liver steatosis will develop non-alcoholic steatohepatitis (NASH), an inflammatory complication associated with higher risk of liver failure and cardiovascular complications leading to death. Projection models suggest that by 2030, more than 2.6 million Canadians will suffer from NASH. Notably, there is currently no standard of care treatment to treat this disease. An important event in the development of NASH is the infiltration of immune cells like macrophages into the liver. These cells contribute to the inflammatory and fibrotic responses that characterize NASH and lead to hepatic dysfunction. Thus, it is critical to understand the mechanisms by which macrophages infiltrate the liver and how this impacts inflammation and subsequent liver dysfunction. Netrin-1 (NTN1) is a protein that induces macrophage retention and allows for their survival in tissues, although its role in the liver is unclear. Preliminary studies from our laboratory suggest that loss of NTN1 in macrophages protects mice fed a high-fat diet from developing NASH, despite the development of obesity. To do this, we have developed various strategies to modulate NTN1 expression in macrophages in mice fed a diet specifically designed to induce NASH. These studies will be the first to determine if NTN1 is a valid drug target to halt or possibly even induce regression of NASH.