This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Non-alcoholic fatty liver disease (NAFLD) is a major health problem in the United States, affecting approximately 20% of the adult population. NAFLD represents a spectrum of liver disease that can be characterized histologically as steatosis, steatohepatitis, fibrosis and cirrhosis. The prevalence of NAFLD is 4-5 times higher in obese than lean persons and is associated with insulin resistance and the metabolic syndrome. However, the mechanism(s) responsible for developing NAFLD in obese persons and the effects of NAFLD itself on metabolic function are not known. This gap in our basic understanding of this disease has made it difficult to identify effective treatments, and the appropriate therapeutic approach to NAFLD is not known. Although weight loss is generally recommended for obese patients with NAFLD, the available data suggest that rapid and marked weight loss increases inflammation, and even liver failure. Therefore, the primary goal of this proposal is to provide a better understanding of: 1) the pathogenesis and pahtophysiology of NAFLD in obese persons, adn 2) the effect of marked weight loss on the histologic and metabolic abnormalities associated with NAFLD. These studies will lay the groundwork for the development of new therapeutic interventions for obese patients with NAFLD. We will test the overall hypotheses that: 1) obesity causes hepatic fat accumulation, because of excessive fatty acid release from adipose tissue and increased FFA avaliability, 2) increased hepatic fat content increases lipid peroxidation and hepatic oxidative stress, which in conjunction with an obesity-related increase in cytokine production, leads to hepatic inflammation, necrosis and fibrosis, 3) increased hepatic fat content and liver inflammation causes insulin-resistant glucose metabolism in the liver and altered hepatic lipoprotein and protein synthesis, and 4) marked weight loss improves the histological and metabolic features of NAFLD, once patients are weight st
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