Childhood obesity and type II diabetes are reaching epidemic proportions in the U.S. particularly among Hispanic and African-American children, and the consequences of this epidemic in terms of nonalcoholic fatty liver disease (NAFLD) are understudied and under appreciated. Hispanic and African-American children are at greater risk for the development of obesity and type II diabetes which are major risk factors for NAFLD. The full impact of this metabolic syndrome will not be realized until these children become adults and develop the long-term consequences of obesity, diabetes and liver disease. The primary objective of this grant is to characterize children at risk for NAFLD and explore possible mechanisms underlying the development of NAFLD in 1000 Hispanic children enrolled in an on-going NIH genome-wide linkage study designed to identify genes that influence the expression of childhood obesity. The long-term objective is to develop an clinical intervention trial to treat the adverse effects of NAFLD in obese children. Hypothesis: Oxidative stress, endotoxemia and systemic inflammation superimposed on hepatic fat accumulation may lead to liver damage in obese children. Specific Aims: 1. To characterize Hispanic children at high risk of developing NAFLD in terms of age, gender, body composition, diet, physical activity, and severity and duration of obesity. 2. To determine the relationships between fasting hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperleptinemia, and elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). 3. To obtain evidence that oxidative stress, endotoxemia and measures of systemic inflammation are associated with elevations in serum ALT and AST. Design: Obese Hispanic children and their nonobese siblings will be screened for NAFLD using serum liver function tests; total sample size will be 1000. We will characterize children at risk for NAFLD and explore possible mechanisms of oxidative stress, endotoxemia and systemic inflammation underlying NAFLD. Methods: Liver function tests, ALT and AST will be analyzed in relation to in-depth phenotyping and genetic linkage analysis performed under the on-going NIH study. Newly proposed tests include chromogenic assays to measure lipid peroxidation end products and endotoxins, and ELISA and RIA to measure cytokine and markers of systemic inflammation.

R03DK066109

2004-01-15

2006-12-31