Pathogenesis of liver injury and hepatic fibrosis in Non-Alcoholic SteatoHepatitis, NASH

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Nonalcoholic steatohepatitis (NASH) is the most common form of liver disease in affluent countries. In Australia at least 3% of the population and 20% of those with obesity have NASH. This poorly understood disease covers a spectrum of liver disorders - from relatively benign presence of excess fat in the liver - to cirrhosis and liver failure. This pattern of liver damage is virtually identical to alcoholic hepatitis, however alcohol consumption is excluded in NASH. It is often associated with type II diabetes , obesity and lipid disorders. Although fatty liver by itself is thought to be innocuous and reversible, a small number of cases with this mild syndrome progress to a more severe form of NASH. One aim of this project is to identify and characterise the factors which trigger injury in a fatty liver and lead to the destruction of liver cells. In response to the initial liver injury in NASH, cells in the liver and from the immune system mount an inflammatory reaction. However this may make the liver even more susceptible to further injury by amplifying the effect of the initial insult. The inflammatory response is controlled by key signalling molecules produced by specific liver and immune cells. The second aim of this project is to identify such molecules and their cellular source and to determine whether they perpetuate the disease processes of NASH. One outcome of liver injury and the consequent inflammatory reaction is that the liver repairs the damage by forming fibres of scar tissue in a process similar to wound healing. When unchecked this process of fibrosis leads to cirrhosis and the development of severe liver complications. The final aim is to gain new insights into the links between liver cell injury, the inflammatory response and fibrosis which will eventually lead to treatments to prevent the initial triggers of this disease and also to interrupt the progression of NASH to more serious fibrotic stage.