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

基本信息

批准号：
9910883
负责人：
Michael J Nash
金额：
$ 3.2万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/9910883
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 Diet Disease Disease Progression Exposure to Fatty acid glycerol esters Fetal Development Fetal Liver Fetus Fibrosis Functional disorder Gene Expression 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 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 therapy design

项目摘要

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/项目摘要非酒精性脂肪肝（NAFLD）是目前世界上最常见的慢性肝病。其病理生理学尚未解决，并且缺乏母亲饮食不良和肥胖的治疗选择。 NAFLD 存在于后代中，但其发生的机制尚不清楚，我们建议确定其影响。母亲西式饮食（WSD）对非人类灵长类动物后代免疫细胞和肝脏表型的影响 (NHP) 模型具有与人类儿童 NAFLD 相似的特征，而 NAFLD 的病理生理学是多因素促炎巨噬细胞 (Mφ) 激活并招募骨髓单核细胞肝脏对其进展至关重要，先天免疫系统源自造血干细胞（HSC），它主要存在于骨髓中，已被证明会影响 HSC 功能，这可能会影响 HSC 的功能。表现为 Mφ 发育和活性的改变，可能促进 NAFLD 的进展。我们的 NHP 模型中的母体 WSD 会增加胎儿脂肪变性（肝脏脂肪），减少骨髓增殖细胞并导致骨髓（先天免疫）细胞产量成比例增加。也存在于暴露于母体 WSD 的幼年 NHP 中，然后在剩余时间内断奶并采用健康饮食此外，我们观察到暴露于母体 WSD 的 NHP 胎儿中 Mφ 细胞因子反应失调。最后，缺氧诱导因子（HIF）-1a 已成为 Mφ 促炎表型的关键驱动因素。我们在小鼠中的初步数据表明，喂食 WSD 的小鼠肝脏 Mφ HIF1A RNA 表达增加，并且 HIF-1a 蛋白稳定已被证明可促进小鼠 Mφ 炎症和纤维化。因此，目前的数据表明，抑制骨髓中的 HIF1a 可能会预防 NAFLD 中的炎症 Mφ 活性。支持这一新假设：母亲 WSD 对子宫内的 HSC 进行差异性编程，以促进持续的骨髓细胞偏斜和下游 Mφ 功能障碍最终导致肝损伤和生命后期的纤维化，并且 Hif1a 对于这种 Mφ 功能障碍是必需的。为了研究这一假设，我们。建议：1) 我们将在胎儿和青少年 NHP 的肝脏中利用 qPCR 和显微技术来确定母亲 WSD 对纤维化、组织炎症和脂质含量的影响。肝脏中招募与驻留 Mφ 的转录表型和比例，以确定相对这些细胞在促进 NAFLD 中的贡献 2) 确定母体 WSD 如何改变转录途径。在 HSC 中负责 NHP 后代 HSC 发育、增殖和 Mφ 表型的变化，包括 Mφ细胞因子反应3)我们将测试小鼠造血细胞中Hif1a的缺失是否是必要的。这些研究将给出母体 WSD 引起的促炎性肝 Mφ 反应和纤维化的改变。对母亲 WSD 如何影响后代 NAFLD 的描述性和机制性见解，这可能会导致新的研究阻碍 NAFLD 进展或减轻这种流行疾病影响的治疗方法。