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: 10612479
• 负责人: JACOB E FRIEDMAN
• 金额: $ 57.39万
• 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/10612479
• 关键词: Acceleration; Adolescent; Adult; Affect; Animal Model; Animals; Area; Automobile Driving; Binding; Bioinformatics; Biological Markers; Blood; Cell Respiration; Child; Childhood; Citric Acid Cycle; Classification; 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; 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; comparison control; 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.

项目摘要 非酒精性脂肪肝病（NAFLD）现在是全球最常见的肝病，几乎影响 40％的肥胖青年和多达10％的一般儿科人口。 NAFLD的某些功能在 儿童和成人，但是纤维化和炎症在门户区域更为常见，并且发生在早期 小儿NAFLD患者比成年人。这预示着早期迅速发展为终末期肝病 成年。对于大多数NAFLD儿童，驱动起源和快速发展的机制 疾病仍然未知。因此，研究特定的潜在模式是有关键的，未满足的需求 儿童独有的肝脏的代谢和分子变化 nafld。肝脂肪生成（DNL）是NAFLD和NAFLD成人肝脂肪变性的主要驱动力 通过胰岛素抵抗加速。此外，通过TCA周期朝着糖异生（GNG）的通量为 增加，促进线粒体损伤，肝损伤和进展到非酒精性脂肪性肝炎 （NASH）通过氧化应激。 DNL和GNG先进的小儿NAFLD的速率是否升高 是未知的。 microRNA（miRNA）是动物模型中DNL和GNG的关键调节剂 NAFLD成年人的潜在生物标志物，但在小儿NAFLD中进行了研究。我们的初步数据 表明与对照组相比，青少年NAFLD患者的血清miR-122和miR-192增加。 但是，现在有可能开发非 - 侵入性儿童生物标志物面板。我们将将新颖的示踪剂，RNA和组织成像方法结合在一起 区分小儿NAFLD的临床意义阶段之间的代谢和分子变化。我们 假设DNL和GNG的速率增加是从NAFLD中进展的原因 儿童，miR-122和miR-192驱动脂肪变性到纳什的发展，而空间异质性 在门户区域基因表达中，纤维化和氧化活性是导致独特的组织病理学 孩子们。在AIM 1中，使用口服示踪剂方法来测量NAFLD和 在属于肥胖或正常体重的健康同龄人中。在AIM 2中，miRNA在血清和 肝脏将确定其作为NAFLD和疾病介体的生物标志物的作用。在AIM 3中，我们将表演 肝活检的高分辨率分子成像，以确定纤维化的丰度和分布， 能量学和成绩单。这项研究将首次确定GNG和DNL是否驱动 小儿NAFLD的发病机理，miRNA是否是循环的生物标志物用于诊断NAFLD和 肝基因表达，氧化代谢和胶原蛋白的周围分布是否 小儿NAFLD患者独有的与代谢评估较差有关。总体而言 优势的优势，我们将确定细胞的病因，早期机制以及潜在的 NAFLD儿童独有的可修改途径和生物标志物。