NHMRC Practitioner Fellowship: The role of obesity, insulin resistance and fatty liver (steatosis) in human disease and strategies to monitor and improve patient outcomes (2011–2015)
The overall objective of this Research Program is to examine in human subjects, the mechanisms by which obesity, insulin resistance and fatty liver impair the response of the liver to injury and inflammation from multiple causes and to develop specific strategies to monitor and improve the outcome of treatment in overweight patients with liver disease. Obesity is the major risk factor for the development of fatty liver, estimated to be present in approximately 20% of the general population. There is now compelling evidence that obesity, insulin resistance and steatosis increase the susceptibility of the liver to inflammation and fibrosis, such as occurs following infection with the hepatitis C virus (HCV). With an epidemic of obesity world-wide, this has very serious implications for human liver disease, particularly as there are no established therapies for the treatment of fatty liver. Along with a role in fibrosis in chronic HCV, obesity and insulin resistance are also negative predictors of response to antiviral treatment. Despite an improvement in the efficacy of antiviral treatment in recent years, approximately 50% of patients infected with HCV genotype 1 and 20% of those with HCV genotype 3 fail to achieve a sustained virologic response (SVR). Strategies to increase the number of patients achieving a sustained response to antiviral treatment are urgently required. Although some studies of the mechanisms of liver injury have been performed in animal models, the available animal models of human fatty liver disease and hepatitis C are inadequate, and necessitate more patient-oriented research using human biologic samples. With my clinical and laboratory expertise in hepatitis C and fatty liver disease, I am in a unique position to successfully address these issues and develop clinically applicable strategies to improve the outcome of patients with chronic liver disease.