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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：
10022108
负责人：
Michael J Nash
金额：
$ 3.25万
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/10022108
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.

抽象/项目总结