Pathophysiologic mechanisms leading to intrahepatic fat accumulation in obese youth

肥胖青年肝内脂肪堆积的病理生理机制

• 批准号: 10395965
• 负责人: Nicola Santoro
• 金额: $ 18.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-21 至 2022-04-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395965
• 关键词: Acids; Address; Adolescent; Adolescent obesity; Adult; Affect; Age; Black Populations; Black race; Body mass index; Carbohydrates; Child; Cirrhosis; Citric Acid Cycle; Clinical; Data; Deuterium Oxide; Development; Diagnostic; Dietary Carbohydrates; Disease; Dyslipidemias; Enrollment; Ethnic Origin; Ethnic group; Etiology; Fasting; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Funding Opportunities; Gender; Glucose; Glycolysis; Hepatic; High Prevalence; Hispanic; Hispanic Populations; Individual; Insulin; Insulin Resistance; Kinetics; Learning; Light; Liver; Liver diseases; Magnetic Resonance Imaging; Malignant neoplasm of liver; Measures; Metabolic; Methods; Morbid Obesity; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Nutritional; OGTT; Obesity; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pediatrics; Plasma; Play; Predisposition; Propionates; Race; Reporting; Retrospective Studies; Risk Factors; Role; Severity of illness; System; Testing; Time; Triglycerides; Youth; base; cardiometabolism; chronic liver disease; early onset; end stage liver disease; ethnic difference; experience; fasting plasma glucose; follow-up; glucose monitor; glucose sensor; insight; intrahepatic; lipid biosynthesis; liver injury; mathematical model; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; obesity in children; pediatric non-alcoholic fatty liver disease; programs; recruit; response; stressor

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.

项目总结