Pathophysiology of fatty liver disease: Understanding inflammation, insulin resistance and iron-overload

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Fatty liver disease is rapidly becoming a serious health concern in domestic animals, captive wildlife and humans. It is a key feature in the metabolic syndrome associated with obesity and the development of insulin resistance. The lifestyle of domestic livestock has been fundamentally changed in captivity, to one that is characterized by abundance of high calorie food and limited physical activity. In the carnivorous mink, fatty liver develops very rapidly, is without symptoms, and often results in death causing significant economic and genetic losses. It is associated with excessive feeding and body fat accumulation, protein-calorie malnutrition, drastic slimming in preparation for breeding, lack of appetite, and rapid mobilization of body fat reserves for milk production; all states of nutritional imbalance. My goal is to understand the underlying biology of fatty liver disease and the role of inflammation in the development of insulin resistance and excessive iron accumulation within the liver. I plan to study in mink, the physiological mechanisms by which liver fat accumulation leads to oxidative stress, liver inflammation, and iron-overload disease. The animal studies will enable us to learn about the organ, tissue and whole animal level manifestations of fatty liver disease and the associated metabolic syndrome. In order to understand the cellular level mechanisms, I will investigate the development, prevention and reversal of insulin resistance and iron storage using liver cell and macrophage cell culture. To study these responses, I will use clinical-chemical, histological, biochemical and molecular methods. I will assess the gene expression and the amount and activity of proteins associated with the early stages of liver inflammation by quantitative real-time polymerase chain reaction, Western blotting and zymography. Understanding the fundamental pathophysiological mechanisms will be critical in the prevention and reversal of this often fatal disease and the associated health and welfare costs. Better metabolic health will in turn result in improved growth and immune function, and optimum reproductive performance, all significant criteria in domestic animal production and endangered species conservation programs. Given the liver’s central role in body fat, blood sugar and iron metabolism and the rapidly increasing global prevalence of the metabolic syndrome this research will have vital application to both domestic animal and human health.