Pathophysiologic mechanisms leading to intrahepatic fat accumulation in obese youth

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Project Summary Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease in pediatrics, affecting about 30% of obese youth. The term NAFLD defines a wide spectrum of disease severity ranging from simple intrahepatic fat accumulation without liver injury (steatosis) to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. A 20-year retrospective study has shown that subjects who develop NAFLD during their youth have about 13 times higher mortality rate for end-stage liver disease than healthy subjects of similar age and gender NAFLD is highly prevalent among Hispanic youth, while non-Hispanic Black (NHB) youth are protected against intrahepatic fat accumulation even in the presence of severe obesity and insulin resistance. Understanding the pathophysiology underlying these differences could shed new light on the mechanisms leading to NAFLD in obese youth. Our preliminary data suggest that Hispanic and NHB obese youth might have a different ability to metabolize carbohydrates (CHO) through glycolysis, with Hispanics showing higher glycolysis than NHB. Therefore, Hispanics might experience a higher rated tricyclic acid cycle (TCA) and hepatic de novo lipogenesis (DNL). In the present study we aim to address the following questions 1) Is the different susceptibility between Hispanics and NHB in developing NAFLD due to a higher capability of Hispanics to metabolize CHO through glycolysis, TCA cycle and DNL? 2) Do these metabolic changes anticipate the onset of the disease in Hispanic youth? 3) Are the higher rates of glycolysis, TCA and DNL driven by high but not- pathologic changes in glucose levels over time? To address our aims we plan to recruit 30 Hispanics and 30 NHB obese youth and to measure glycolysis by using a new method to assess lactate kinetics and to determine the TCA cycle and DNL by using 13C-Propionate and D2O. Moreover, we will assess glycolysis and intrahepatic fat content in a group of 150 Hispanic obese youth without fatty liver at baseline every 12 months for two years to determine whether higher glycolytic rates precede intrahepatic fat accumulation. To assess whether metabolic changes in glycolysis are driven by higher but not-pathologic glucose levels, we will measure glucose changes over ten days every six months by using a continuous glucose monitoring system. If successful these studies will provide novel insight into the pathogenesis of pediatric NAFLD and will open new avenues to test novel therapeutic approaches.