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.

项目总结 非酒精性脂肪性肝病(NAFLD)现在是世界上最常见的肝病，影响到近 40%的肥胖青年和高达10%的普通儿科人口。NAFLD的一些特征在以下方面类似 儿童和成人，然而纤维化和炎症在门脉区域更常见，并且更早发生在 儿童非酒精性脂肪肝患者明显多于成人。这预示着在早期迅速发展为终末期肝病。 成人期。对于大多数患有NAFLD的儿童来说，推动其发生和快速发展的机制 疾病仍然未知。因此，有一个关键的，尚未得到满足的需要，研究特定的潜在模式 肝脏的代谢和分子变化是儿童所特有的发育和进展 NAFLD。肝脏新生脂肪生成(DNL)是成人NAFLD患者肝脏脂肪变性的主要驱动因素 会因胰岛素抵抗而加速。此外，通过TCA循环走向糖异生(GNG)的通量是 增加，促进线粒体损伤、肝损伤和进展为非酒精性脂肪性肝炎 (NASH)通过氧化应激。DNL和GNG比率升高是否以及如何促进儿童NAFLD 是未知的。在动物模型中，microRNAs(MiRNA)是DNL和GNG的关键调节因子，并出现为 成人非酒精性脂肪肝的潜在生物标志物，但在儿童非酒精性脂肪肝中研究不足。我们的初步数据 显示青少年NAFLD患者血清miR-122和miR-192较对照组升高。 然而，在儿童NAFLD中完整的循环miRNAs图谱现在有可能发展成一种非 儿童侵入性生物标记物面板。我们将结合新的示踪剂、RNA和组织成像方法来 区分儿童NAFLD临床显著阶段的代谢和分子变化。我们 假设DNL和GNG的增加是NAFLD进展的原因 儿童，miR-122和miR-192推动脂肪变性发展为NASH，并且这种空间异质性 在门静脉区域，基因表达、纤维化和氧化活性是导致肝细胞癌独特组织病理学的原因。 孩子们。在目标1中，使用口服示踪剂方法来测量患有NAFLD的青少年和 在被归类为肥胖或正常体重的健康同龄人中。在目标2中，血清和血清中的miRNA分析 肝脏将决定它们作为NAFLD生物标志物和疾病介体的作用。在目标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是否会推动 儿童NAFLD的发病机制，miRNAs是否是诊断NAFLD的循环生物标志物 肝门周围是否分布肝脏基因表达、氧化代谢和胶原形成 儿童NAFLD患者所特有的代谢评估较差。集体地，通过采取 利用独特的工具，我们将确定亚细胞病因学、早期机制和潜在的 NAFLD儿童特有的可修改的途径和生物标记物。