Maternal Obesity and Pediatric NAFLD: Fetal Origins and Long-term outcomes in Non Human Primates

母亲肥胖和儿童 NAFLD：非人类灵长类动物的胎儿起源和长期结果

• 批准号: 10646292
• 负责人: JACOB E FRIEDMAN
• 金额: $ 57.26万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646292
• 关键词: 3 year old; ATAC-seq; Adolescent; Adult; Affect; Age; Animals; Anti-Inflammatory Agents; Bile Acids; Binding; Birth; Bone Marrow; Cells; Child; Childhood; Clinical; Collagen; Consumption; Critical Pathways; Data; Deposition; Development; Diet; Down-Regulation; Embryo; Epigenetic Process; Ethnic Origin; Fatty acid glycerol esters; Fetal Liver; Fetus; Fibrosis; Gene Expression; Genetic Transcription; Glycolysis; Goals; Hematopoietic stem cells; Hepatic; Hepatic Stellate Cell; Hepatocyte; Human; Immune; Immunoprecipitation; Impairment; In Vitro; Infant; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-4; Life; Liver; Liver Fibrosis; Longevity; Longitudinal Studies; Macrophage; MicroRNAs; Modeling; Modification; Molecular; Obesity; Outcome; Overweight; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Population; Portal triad; Predisposition; Prevalence; Production; Race; Risk; Risk Factors; Role; Signal Transduction; Signaling Protein; Site; Socioeconomic Status; Testing; Toddler; Weaning; Yolk Sac; Youth; bile acid metabolism; cell injury; crosslink; crosslinking and immunoprecipitation sequencing; cytokine; emerging adult; end stage liver disease; epigenome; fetal; healing; in utero; juvenile animal; liver injury; liver metabolism; maternal obesity; migration; monocyte; mother nutrition; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; nonhuman primate; novel; obese mothers; offspring; pediatric non-alcoholic fatty liver disease; postnatal; programs; recruit; response; single-cell RNA sequencing; stellate cell; transcriptome sequencing; western diet

PROJECT SUMMARY The prevalence of maternal overweight and obesity continues to increase in the U.S. and spans the spectrum of age, race and ethnicity, and socioeconomic status. Alarmingly, 1 in 10 infants and toddlers are obese, and 1 in 5 youth are both obese and at-risk for pediatric Non-alcoholic fatty liver disease (NAFLD). NAFLD can begin in utero with longitudinal studies showing an increased risk of NAFLD in adolescents born to obese mothers. Some features of NAFLD are similar in children and adults, yet portal fibrosis and inflammation are more common in pediatric NASH patients than adult patients, and portends a rapid progression to end-stage liver disease in early adulthood for reasons that remain poorly understood. Our group has spent the past decade developing and characterizing a sophisticated nonhuman primate (NHP) model of high fat/calorically dense maternal diet consumption that has critically important developmental and physiological similarities to humans. Data from our well-characterized NHP model demonstrate that maternal Western-style diet (MWSD) triggers fetal hepatic collagen deposition in the portal triad and stellate cell activation that persists in 3-year-old (3YO) juvenile animals, despite switching to a healthy chow diet at weaning. Notably, 2 miRNAs with critical roles in liver metabolism and inflammatory responses were significantly increased (miR-122) or decreased (miR-34a) in fetal liver and partially normalized when obese mothers were switched to a healthy chow diet. Our results suggest these miRNAs are diet-sensitive and candidate targets for epigenetic priming of NAFLD early in life. Our preliminary data in 3YO NHP offspring also show that MWSD reprograms hematopoietic stem cell progenitors (HSPC)s and bone marrow derived macrophages (BMDM) to a glycolytic phenotype and a blunted response to IL-4, suggesting decreased anti-inflammatory capacity and impaired Mφ ability to assume a reparative phenotype. Given the importance of M2-like Mφ for healing liver injury,our overall hypothesis is that MWSD alters miRNAs in liver in parallel with epigenetically reprogrammed HSPC and liver Mφ before birth. This leads to ongoing production of hyper-inflammatory Mφ and the inability to resolve liver injury across the lifespan. The overarching goal of this proposal is to understand the mechanistic basis by which MWSD drives epigenetic remodeling and the pathogenesis for NAFLD beginning in utero. In this revised application, our Aims are to: 1) Test the hypothesis that MWSD alters binding of fetal miR-34a, and miR-122 to specific targets in fetal liver, and identify macrophage sub-sets in Juvenile livers using single cell RNAseq; 2) Test the hypothesis that MWSD drives pro-inflammatory functions in isolated fetal and 3YO HSPC and liver Mφ through distinct transcriptional and epigenetic mechanisms. 3) Test the hypothesis that MWSD disrupts BA signaling and HNF4α in MWSD hepatocytes and preferentially affects periportal hepatocytes in fetal and post-natal livers.Taken together, using fetal and Juvenile NHP, which have developmental features similar to humans, we will decipher how MWSD exposure triggers epigenetic and inflammatory modifications in HSPC and liver Mφ that drive novel pathways underlying pediatric NAFLD.

项目概要 在美国，孕产妇超重和肥胖的患病率持续增加，并且跨越了整个国家 年龄、种族和民族以及社会经济地位的范围。令人震惊的是，十分之一的婴儿和幼儿 肥胖，五分之一的青少年既肥胖又面临儿科非酒精性脂肪肝 (NAFLD) 的风险。 NAFLD 可以在子宫内开始，纵向研究显示出生的青少年患 NAFLD 的风险增加 肥胖的妈妈们。 NAFLD 的一些特征在儿童和成人中相似，但门脉纤维化和炎症 在儿童 NASH 患者中比成人患者更常见，并且预示着快速进展至终末期 成年早期患有肝病，其原因仍知之甚少。我们集团过去十年 开发和表征复杂的高脂肪/热量密度的非人类灵长类动物 (NHP) 模型 母亲的饮食消费与人类具有极其重要的发育和生理相似性。 来自我们充分表征的 NHP 模型的数据表明，母亲的西式饮食 (MWSD) 会引发 胎儿肝门三联体中的胶原沉积和 3 岁 (3YO) 中持续存在的星状细胞活化 幼年动物，尽管在断奶时改用健康的食物。值得注意的是，2 个 miRNA 在 肝脏代谢和炎症反应显着增加（miR-122）或减少（miR-34a） 当肥胖母亲改用健康饮食时，胎儿肝脏和部分正常化。我们的结果表明 这些 miRNA 是饮食敏感的，也是生命早期 NAFLD 表观遗传启动的候选靶点。我们的 3YO NHP 后代的初步数据还表明 MWSD 重新编程造血干细胞祖细胞 （HSPC）和骨髓源性巨噬细胞（BMDM）对糖酵解表型和对糖酵解的反应迟钝 IL-4，表明抗炎能力下降，Mφ修复能力受损 表型。鉴于 M2 样 Mφ 对于治疗肝损伤的重要性，我们的总体假设是 MWSD 改变 肝脏中的 miRNA 与出生前表观遗传重编程的 HSPC 和肝脏 Mφ 平行。这导致 持续产生高炎症 Mφ 且无法在整个生命周期解决肝损伤。这 该提案的总体目标是了解 MWSD 驱动表观遗传的机制基础 NAFLD 的重塑和发病机制从子宫内开始。在此修订后的应用程序中，我们的目标是：1) 检验 MWSD 改变胎儿 miR-34a 和 miR-122 与胎儿肝脏中特定靶标的结合的假设，以及 使用单细胞 RNAseq 识别幼年肝脏中的巨噬细胞亚群； 2）检验MWSD的假设 通过不同的转录驱动离体胎儿和 3YO HSPC 以及肝脏 Mφ 的促炎功能 和表观遗传机制。 3) 检验MWSD破坏MWSD中的BA信号传导和HNF4α的假设 肝细胞，并优先影响胎儿和产后肝脏中的门静脉周围肝细胞。综上所述，使用 胎儿和青少年 NHP 具有与人类相似的发育特征，我们将解密 MWSD 的原理 暴露会触发 HSPC 和肝脏 Mφ 的表观遗传和炎症修饰，从而驱动新的途径 潜在的儿科 NAFLD。