Hepatic FOXA3 Links NAFLD to Atherosclerosis

肝脏 FOXA3 将 NAFLD 与动脉粥样硬化联系起来

基本信息

批准号：
10364733
负责人：
Yanqiao Zhang
金额：
$ 51.12万
依托单位：
NORTHEAST OHIO MEDICAL UNIVERSITY
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：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364733
关键词：
Ablation Anti-Inflammatory Agents Antioxidants Apolipoprotein A-I Apolipoprotein E Arylesterase Atherosclerosis Attenuated Cardiovascular Diseases Cause of Death Cessation of life Cholesterol Homeostasis Data Developed Countries Development Diabetes Mellitus Diabetic mouse Disease Extrahepatic Fatty Acids Genes HNF4A gene Health Hepatic Hepatocyte High Density Lipoproteins High Fat Diet Human Incidence Inflammation Inflammatory Response Kupffer Cells Lead Link Lipids Lipoproteins Liver Liver Cirrhosis Liver Dysfunction Liver diseases Low-Density Lipoproteins Mediating Metabolic stress Metabolism MicroRNAs Mus Nuclear Hormone Receptors Obese Mice Obesity Palmitates Pathogenesis Patients Pilot Projects Plasma Play Primary carcinoma of the liver cells Proteins Regulation Repression Risk Factors Role Signal Pathway Testing Triglyceride Metabolism Triglycerides Very low density lipoprotein atherogenesis base chronic liver disease db/db mouse diabetic improved insight knock-down lipid metabolism loss of function member non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutic intervention overexpression prevent reverse cholesterol transport simple steatosis stellate cell transcription factor transcriptome sequencing treatment strategy

项目摘要

Project Summary Project Summary: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, which includes simple steatosis (NAFL) and non-alcoholic steatohepatitis (NASH). NAFLD not only causes liver dysfunctions but also induces extra-hepatic complications. Accumulating data indicate that cardiovascular disease (CVD) is the major cause of deaths in NAFLD patients. So far, the mechanism underlying the development of NAFLD is poorly understood. In addition, it is unclear why NAFLD patients have increased incidence of CAD. Forkhead box A3 (FOXA3) is a transcription factor whose function in lipid or lipoprotein metabolism has not been established. Our preliminary studies show that hepatic FOXA3 expression is markedly reduced under common metabolic stress. Using over-expression or knockdown approaches, we show that hepatic FOXA3 regulates hepatic lipid and plasma HDL levels as well as the expression of HDL-associated proteins. These novel data suggest that dysregulation of hepatic FOXA3 may play an important role in the pathogenesis of both NAFLD and CVD. To test this hypothesis, we will use both gain- and loss-of-function approaches. Completion of the proposed studies may uncover a novel role of hepatic FOXA3 in the development of NAFLD and atherosclerosis and may offer novel insights into the mechanism by which NAFLD is a risk factor for CAD.

项目概要项目概要：非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病之一世界范围内，包括单纯性脂肪变性（NAFL）和非酒精性脂肪性肝炎（NASH）。非酒精性脂肪肝不仅不仅会导致肝功能障碍，还会引起肝外并发症。不断积累的数据表明心血管疾病（CVD）是 NAFLD 患者死亡的主要原因。到目前为止，其底层机制人们对 NAFLD 的发展知之甚少。此外，尚不清楚为什么 NAFLD 患者增加冠心病的发病率。叉头框 A3 (FOXA3) 是一种转录因子，其在脂质或脂蛋白中发挥作用新陈代谢尚未建立。我们的初步研究表明肝脏 FOXA3 表达显着在常见的代谢应激下减少。使用过度表达或敲低方法，我们证明肝脏 FOXA3 调节肝脂质和血浆 HDL 水平以及 HDL 相关蛋白的表达蛋白质。这些新数据表明肝脏 FOXA3 的失调可能在 NAFLD 和 CVD 的发病机制。为了检验这个假设，我们将使用功能增益和功能丧失接近。完成拟议的研究可能会揭示肝脏 FOXA3 在发育中的新作用 NAFLD 和动脉粥样硬化的关系，并可能为 NAFLD 作为危险因素的机制提供新的见解对于 CAD。