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.

项目概要 非酒精性脂肪性肝病 (NAFLD) 目前是全球最常见的肝病，影响近乎 40% 的肥胖青少年和高达 10% 的一般儿童人群。 NAFLD 的一些特征相似 儿童和成人，但纤维化和炎症在汇管区更常见，并且发生得更早。 儿童 NAFLD 患者多于成人。这预示着早期肝病会迅速进展为终末期肝病。 成年期。对于大多数患有 NAFLD 的儿童来说，驱动 NAFLD 起源和快速进展的机制 疾病仍然未知。因此，研究特定的潜在模式是一个关键的、未满足的需求。 肝脏的代谢和分子变化是儿童特有的发育和进展的基础 非酒精性脂肪性肝病。肝脏从头脂肪生成 (DNL) 是成人 NAFLD 和肝脏脂肪变性的主要驱动因素 胰岛素抵抗会加速这一过程。此外，通过 TCA 循环进行糖异生 (GNG) 的通量为 增加，从而促进线粒体损伤、肝损伤以及进展为非酒精性脂肪性肝炎 (NASH) 通过氧化应激。 DNL 和 GNG 率升高是否以及如何促进儿童 NAFLD 未知。 MicroRNA (miRNA) 是动物模型中 DNL 和 GNG 的关键调节因子，并逐渐成为 成人 NAFLD 的潜在生物标志物，但在儿科 NAFLD 中的研究还不够。我们的初步数据 研究表明，与对照组相比，青少年 NAFLD 患者的血清 miR-122 和 miR-192 有所增加。 然而，现在有可能开发出儿科 NAFLD 中循环 miRNA 的完整谱图。 儿童侵入性生物标志物组。我们将结合新颖的示踪剂、RNA 和组织成像方法来 区分儿科 NAFLD 临床显着阶段的代谢和分子变化。我们 假设 DNL 和 GNG 发生率增加是 NAFLD 进展的致病途径 儿童，miR-122 和 miR-192 驱动脂肪变性发展为 NASH，并且空间异质性 在汇管区，基因表达、纤维化和氧化活性是导致汇管区独特的组织病理学的原因。 孩子们。在目标 1 中，使用口服示踪剂方法来测量患有 NAFLD 的青少年的 DNL 和 GNG 在被归类为肥胖或正常体重的健康同龄人中。在目标 2 中，血清中的 miRNA 分析和 肝脏将决定它们作为 NAFLD 生物标志物和疾病介质的作用。在目标 3 中，我们将执行 肝脏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 儿科 NAFLD 的发病机制，miRNA 是否是诊断 NAFLD 的循环生物标志物，以及 肝脏基因表达、氧化代谢和胶原蛋白形成的门静脉周围分布是否 儿科 NAFLD 患者特有的代谢评估较差。总的来说，通过采取 凭借独特的工具，我们将确定亚细胞病因、早期机制和潜在的 NAFLD 儿童特有的可修改途径和生物标志物。