The Impact of Maternal Western Style Diet on Immune Cell Function and Development of Non-Alcoholic Fatty Liver Disease

母亲西式饮食对免疫细胞功能和非酒精性脂肪肝发展的影响

• 批准号: 10461980
• 负责人: Michael J Nash
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2023-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461980
• 关键词: 3 year old; Adolescent; Affect; Attenuated; Automobile Driving; Biological Assay; Bone Marrow; Bone Marrow Cells; Cardiovascular Diseases; Cell Proliferation; Cell physiology; Cells; Data; Development; Disease; Disease Progression; Exposure to; Fatty acid glycerol esters; Fetal Development; Fetal Liver; Fetus; Fibrosis; Functional disorder; Gene Expression; Gene Expression Profile; Genetic Transcription; HIF1A gene; Health; Hematopoietic; Hematopoietic stem cells; Hepatic; Histologic; Histology; Human; Hypoxia Inducible Factor; Immune; Immune response; Immune system; Inflammation; Inflammatory; Innate Immune System; Knock-out; Lead; Learning; Life; Link; Lipids; Lipopolysaccharides; Liver; Liver Fibrosis; Measures; Mediating; Metabolic Diseases; Metabolism; Methods; Microscopic; Modeling; Mothers; Mus; Myelogenous; Myeloid Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathology; Pathway interactions; Phenotype; Physiology; Population; Pregnancy; Prevalence; Primary carcinoma of the liver cells; Production; Program Development; Proteins; RNA analysis; Risk Factors; Role; Stem Cell Development; Techniques; Testing; Tissues; Translating; Umbilical Cord Blood; United States; Weaning; cell type; chronic liver disease; cytokine; dietary control; fetal; good diet; in utero; insight; lipid biosynthesis; liver inflammation; liver injury; liver repair; liver transplantation; macrophage; maternal obesity; monocyte; mother nutrition; nano-string; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; nonhuman primate; novel; novel therapeutic intervention; obese mothers; offspring; pediatric non-alcoholic fatty liver disease; pediatric patients; postnatal; prevent; programs; recruit; response; stem cell function; therapy design; western diet

Abstract/Project Summary Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease worldwide. However, its pathophysiology is unresolved and treatment options are lacking. Poor maternal diet and obesity promote NAFLD in offspring, but the mechanisms by which this occurs are not clear. We propose to identify the impact of maternal western style diet (WSD) on offspring immune cell and liver phenotypes in a non-human primate (NHP) model with features similar to human pediatric NAFLD. While the pathophysiology of NAFLD is multifactorial, pro-inflammatory macrophage (Mφ) activation and recruitment of bone marrow monocytes to the liver are critical for its progression. The innate immune system is derived from hematopoietic stem cells (HSCs), which reside primarily in the bone marrow. Maternal diet has been shown to skew HSC function, which may manifest as alterations in Mφ development and activity, potentially promoting NAFLD progression. We find that maternal WSD in our NHP model increases fetal steatosis (liver fat), decreases proliferation of bone marrow cells and causes a proportional increase in myeloid (innate immune) cell production. Strikingly, these phenotypes are also present in juvenile NHP exposed to maternal WSD then weaned onto a healthy diet for the remainder of life. In addition, we observe dysregulated Mφ cytokine response in NHP fetuses exposed to maternal WSD. Finally, hypoxia-inducible factor (HIF)-1a has emerged as a critical driver of the Mφ pro-inflammatory phenotype. Our preliminary data in mice show that mice fed a WSD have increased hepatic Mφ HIF1A RNA expression and HIF-1a protein stabilization has been shown to promote Mφ inflammation and fibrosis in mice. This suggests that inhibiting HIF1a in bone marrow may prevent inflammatory Mφ activity in NAFLD. Therefore, current data supports the novel hypothesis that maternal WSD differentially programs HSCs in utero to promote persistent myeloid cell skewing and downstream Mφ dysfunction that ultimately drives liver damage and fibrosis later in life, and that Hif1a is necessary for this Mφ dysfunction. To investigate this hypothesis we propose to: 1) We will utilize qPCR and microscopic techniques in livers from fetal and juvenile NHPs to determine the impact of maternal WSD on fibrosis, tissue inflammation and lipid content. We will also investigate the transcriptional phenotypes and proportions of recruited vs. resident Mφ in livers, to determine the relative contributions of these cells in promoting NAFLD. 2) Identify how maternal WSD alters transcriptional pathways in HSCs responsible for shifts in HSC development, proliferation, and Mφ phenotypes in NHP offspring, including Mφ cytokine response. 3) We will test whether deletion of Hif1a in hematopoietic cells in mice is necessary for maternal WSD induced alterations in pro-inflammatory hepatic Mφ response and fibrosis. These studies will give descriptive and mechanistic insight into how maternal WSD impacts offspring NAFLD, which may lead to new therapeutic approaches to hinder NAFLD progression or attenuate the impact of this prevalent disease.

摘要/项目摘要 但是，非酒精性脂肪肝疾病（NAFLD）现在是最常见的慢性利物质。 它的病理生理学尚未解决，缺乏治疗选择。 nafld在后代，但我们建议确定影响的机制。 非人类灵长类动物中后代免疫细胞和肝表型的母亲西方风格饮食（WSD） （NHP）具有类似于人类儿科NAFLD的特征的模型。 多因素，促炎巨噬细胞（Mφ）激活和骨髓单核细胞的募集和募集 肝脏对其进展至关重要。 主要存在于骨髓中。 表现为Mφ发育和活性的改变，可能促进NAFLD的进展 NHP模型中的母体WSD增加了胎儿脂肪变性（肝脏脂肪），可降低骨髓的增殖 细胞并引起髓样（先天免疫）细胞产生的比例增加 也存在于少年NHP中，暴露于母体WSD，然后在健康饮食中脱颖而出 生命。此外，我们观察到暴露于母体WSD的NHP胎儿中的非注册Mφ细胞因子反应。 最后，缺氧诱导因子（HIF）-1a已成为Mφ促炎表型的关键驱动力。 我们在小鼠中的初步数据表明，喂养WSD的小鼠肝M或 HIF-1A蛋白稳定已显示出促进小鼠的Mφ炎症和纤维化 抑制骨髓中的HIF1A可能会预防NAFLD中的Mφ活性 支持新颖的假设，即母亲WSD差异地编程子宫内的HSC以促进 持续的髓样细胞偏斜和下游Mφ功能障碍，最终驱动肝脏损伤和 以后的纤维化，HIF1A对于Mφ功能障碍是必需的。 提议：1）我们将利用从胎儿和果汁到肝脏中的QPCR和微观技术 确定母体WSD对纤维化，组织炎症和脂质含量的影响。 与肝脏中的招募和居住的Mφ的转录表型和比例，以确定相对 细胞在促进NAFLD中的贡献。 在负责HSC开发，繁殖和Mφ表型的HSC中 Mφ细胞因子resupone 3）我们将测试小鼠造血细胞中HIF1A的缺失 母体WSD诱导的促肝Mφ反应和纤维化的改变。 描述性和机械洞察力对产妇WSD如何影响后代NAFLD，这可能导致新的 阻碍NAFLD进展或减轻这种普遍疾病的影响的治疗方法。