Understanding the metabolic pathology of pediatric obesity and NAFLD

了解儿童肥胖和 NAFLD 的代谢病理学

• 批准号: 10453952
• 负责人: JACOB E FRIEDMAN
• 金额: $ 59.6万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-22 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453952
• 关键词: Adolescent; Adult; Affect; Animal Model; Animals; Area; Automobile Driving; Bioinformatics; Biological Markers; Blood; Cell Respiration; Child; Childhood; Citric Acid Cycle; Collagen; Control Groups; Data; Development; Diagnosis; Disease; Disease Progression; Etiology; Event; Fasting; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Gene Expression; Genes; Genetic Transcription; Gluconeogenesis; Glucose; Glycerol; Hepatic; Heterogeneity; Histopathology; Imaging Device; Immunoprecipitation; Inflammation; Insulin Resistance; Lipids; Liver; Liver Fibrosis; Liver diseases; Location; Measures; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic Pathway; Methods; MicroRNAs; Mitochondria; Molecular; Nutrient; Obesity; Oral; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pediatric Surgical Procedures; Population; Proteins; RNA; Resolution; Role; Sampling; Serum; Severity of illness; Spatial Distribution; Stress; Testing; Time; Tissue imaging; Tissues; Tracer; Transcript; Variant; Very low density lipoprotein; Weight; Youth; biomarker panel; circulating biomarkers; circulating microRNA; clinically significant; disorder prevention; emerging adult; end stage liver disease; imaging modality; lipid biosynthesis; liver biopsy; liver injury; molecular imaging; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel marker; obesity in children; pediatric non-alcoholic fatty liver disease; pediatric patients; peer; potential biomarker; sugar; therapeutic development; therapeutic target; tool

PROJECT SUMMARY Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disease worldwide and affects nearly 40% of obese youth and up to 10% of the general pediatric population. Some features of NAFLD are similar in children and adults, yet fibrosis and inflammation are more common in the portal zone and occur earlier in pediatric NAFLD patients than adults. This portends a rapid progression to end-stage liver disease in early adulthood. For the majority of children with NAFLD, mechanisms driving the origin and rapid progression of disease remain unknown. Thus, there is a critical, unmet need to study the specific underlying patterns of metabolic and molecular changes in the liver underlying development and progression unique to children with NAFLD. Hepatic de novo lipogenesis (DNL) is a primary driver of hepatic steatosis in adults with NAFLD and is accelerated by insulin resistance. Additionally, flux through the TCA cycle toward gluconeogenesis (GNG) is increased, which promotes mitochondrial damage, liver injury, and progression to nonalcoholic steatohepatitis (NASH) through oxidative stress. Whether and how elevated rates of DNL and GNG advance pediatric NAFLD is unknown. MicroRNAs (miRNA) are critical regulators of DNL and GNG in animal models and emerging as potential biomarkers in adults with NAFLD but are understudied in pediatric NAFLD. Our preliminary data show that serum miR-122 and miR-192 are increased in adolescent NAFLD patients compared to controls. However, a complete profile of circulating miRNAs in pediatric NAFLD is now possible to develop a non- invasive biomarker panel for children. We will combine novel tracer, RNA, and tissue imaging methods to discriminate the metabolic and molecular changes among clinically-significant stages of pediatric NAFLD. We hypothesize that increased rates of DNL and GNG are causative pathways for progression from NAFLD in children, that miR-122 and miR-192 drive the development of steatosis to NASH, and that spatial heterogeneity in portal zone gene expression, fibrosis, and oxidative activity are responsible for the unique histopathology in children. In aim 1, an oral tracer approach is used to measure DNL and GNG in adolescents with NAFLD and in healthy peers who are classified as either obese or normal weight. In aim 2, miRNA analyses in serum and liver will determine their role as biomarkers for NAFLD and mediators of the disease. In aim 3, we will perform high resolution molecular imaging of liver biopsies to determine the abundance and distribution of fibrosis, energetics, and transcripts. This study will establish for the first time whether GNG and DNL drive the pathogenesis of pediatric NAFLD, whether miRNAs are circulating biomarkers for diagnosis of NAFLD, and whether the periportal distribution of liver gene expression, oxidative metabolism, and collagen formation unique to pediatric NAFLD patients are associated with worse metabolic assessments. Collectively, by taking advantage of unique tools, we will identify the sub-cellular etiology, early mechanisms, and potentially modifiable pathways and biomarkers unique to children with NAFLD.

项目总结