Liver Positron Emission Tomography (PET) Study of Non Alcoholic Fatty Liver Disease

This study involves a multidisciplinary approach that will address the metabolic mechanisms responsible for Non-alcoholic Fatty Liver Disease (NAFLD) in humans. Nonalcoholic fatty liver disease (NAFLD) has become an important public health problem in many industrialized countries because of its high prevalence, potential progression to severe liver disease, and association with cardiometabolic abnormalities, including diabetes, the metabolic syndrome, dilated cardiomyopathy, and coronary heart disease. Although obesity is an important risk factor for NAFLD many obese persons have minimal or no steatosis. The mechanism responsible for the pathogenesis of steatosis is not known, but must involve one or more of the following: 1. Increased hepatic fatty acid (FA) delivery 2. Decreased hepatic FA oxidation 3. Increased de novo lipogenesis (DNL) 4. Inadequate hepatic triglyceride secretion We hypothesize that alterations in all of these metabolic processes are involved in the pathogenesis of NAFLD. However, a comprehensive evaluation of these factors in individual cohorts of subjects has never been performed, and the ability to measure hepatic FA oxidation in vivo in human subjects has not been available. The following Specific Aims will be evaluated in obese women with and without NAFLD, who are scheduled for bariatric surgery: 1. Determine hepatic FA uptake and oxidation by using novel PET techniques in combination with measurements of DNL using stable isotope tracers and by assessing liver tissue FA oxidative capacity by evaluating gene expression of FA oxidative enzymes and mitochondrial content. 2. Determine hepatic fatty acid delivery by using stable isotope tracers to assess the rate of free FA (FFA) release into plasma and cellular biology methods to determine the expression and protein content of the major tissue FA transporter (CD36). 3. Determine hepatic very-low-density lipoprotein TG (VLDL-TG) secretion rate by using stable isotope tracers. 4. Determine liver histology and factors involved in inflammation and fibrosis by using routine staining and immunohistochemistry.