PPARa and related nuclear receptors in non-alcoholic fatty liver disease

PPARa 和相关核受体在非酒精性脂肪肝中的作用

基本信息

批准号：
10576286
负责人：
MITCHELL A. LAZAR
金额：
$ 35.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576286
关键词：
Address Affect Agonist Amino Acids Atherosclerosis Binding Binding Sites Biology Cardiometabolic Disease Cardiovascular system Cell model Cessation of life Choline Deficiency Chromatin Cirrhosis Clinical DNA DNA Binding DNA Binding Domain DNA Sequence Data Diabetes Mellitus Direct Repeats Disease Disease Progression Drug Targeting Drug usage Environment Event Fatty Liver Fibrates Fibrosis Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genetic Models Genetic Polymorphism Genetic Risk Genetic Variation Genetic study Genome Genomic approach Genomics Hepatic Hepatocyte High Fat Diet Hormones Human Human Genetics Hypertriglyceridemia Inbred Strains Mice Inflammation Knockout Mice Ligand Binding Domain Link Liver Liver Failure Liver Fibrosis Minority Modeling Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity Epidemic Outcome PPAR alpha Pathogenesis Pathology Patients Peroxisome Proliferator-Activated Receptors Persons Pharmaceutical Preparations Phase Phenotype Population Prevalence Primary carcinoma of the liver cells Public Health Regulator Genes Risk Reduction Role Sampling Serum Single Nucleotide Polymorphism Site Techniques Testing Therapeutic Time Tissues Triglycerides Untranslated RNA Variant Wild Type Mouse clinically relevant dietary disorder risk drug development environmental change experimental study genetic approach genetic association genetic variant genome-wide improved in vivo individualized medicine innovation interest lipid metabolism liver injury mortality mouse model new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis receptor function response simple steatosis tool transcription factor treatment response

项目摘要

PROJECT SUMMARY/ABSTRACT The epidemic of obesity and type 2 diabetes has increased prevalence of associated cardiometabolic diseases including elevated serum triglycerides (TGs) and non-alcoholic fatty liver disease (NAFLD). There is resurgent interest in drugs targeting the hepatic nuclear receptor PPARα. Such fibrate drugs are already used in hypertriglyceridemia, and there is new appreciation that TGs independently cause atherosclerotic cardiovascular disease such that lowering TGs reduces risk. Furthermore, PPAR agonists may be among the first drugs approved for NAFLD. Adverse clinical outcomes in NAFLD like cirrhotic liver failure, hepatocellular carcinoma, and liver-related death are all closely linked to hepatic fibrosis. Our preliminary data in a NAFLD mouse model show unexpectedly that PPARα deficiency and PPARα agonist treatment both fail to change hepatic steatosis, but markedly affect fibrosis (increasing and decreasing it, respectively). PPARα functions in hepatocytes to bind regulatory DNA and affect expression of key genes in lipid metabolism. The related nuclear receptor HNF4α is not a drug target, yet regulates similar genes and binds similar regulatory DNA. We hypothesize that the interplay of PPARα and HNF4α in DNA binding affects hepatocyte gene regulation, relevant to the pathogenesis and therapeutics of NAFLD. Our experiments probe genome-wide nuclear receptor binding sites and gene regulation, in normal and steatotic livers, basally and in response to drugs. Aim 1 defines the interdependency of PPARα and HNF4α in liver gene regulation, using mouse models deficient in either or both. Aim 2 extends these studies of PPARα and HNF4α to NAFLD, in both mouse models and human biospecimens. Aim 3 deploys the powerful tools of genetics to characterize PPARα and HNF4α interplay in sequence-specific DNA binding. By comparing inbred mouse strains, natural polymorphisms affecting binding motifs will reveal mechanisms for selective and common DNA binding by PPARα and HNF4α. In human liver samples, we will test the hypothesis that that non- coding genetic variants in PPARα/HNF4α genomic binding sites underlie some differences among people in TG levels, NAFLD, and response of these to PPARα agonist drugs. Beyond this potential clinical relevance, these studies use innovative genomic and genetic approaches to address key unanswered questions in the biology of PPARα, including its interplay with related nuclear receptors.

项目概要/摘要肥胖和 2 型糖尿病的流行增加了相关心脏代谢疾病的患病率包括血清甘油三酯（TG）升高和非酒精性脂肪肝（NAFLD）有复发。人们对针对肝核受体 PPARα 的药物产生了兴趣，此类贝特类药物已用于治疗。高甘油三酯血症，并且有新认识认为甘油三酯独立导致动脉粥样硬化性心血管疾病此外，PPAR 激动剂可能是首批药物之一。批准用于 NAFLD 的不良临床结果，如肝硬化肝衰竭、肝细胞癌、和肝脏相关的死亡都与肝纤维化密切相关。我们在 NAFLD 小鼠模型中的初步数据。出人意料地表明 PPARα 缺乏和 PPARα 激动剂治疗均未能改变肝脂肪变性，但显着影响纤维化（分别增加和减少肝细胞中 PPARα 的结合功能）。脂质代谢中关键基因的调控 DNA 和表达影响是相关的核受体 HNF4α。不是药物靶点，但调节相似的基因并结合相似的调控 DNA。 PPARα和HNF4α在DNA结合中影响肝细胞基因调控，与发病机制和我们的实验探索全基因组核受体结合位点和基因调控，在正常和脂肪变性肝脏中，基础和对药物的反应目标 1 PPARα 的相互依赖性。和 HNF4α 在肝脏基因调控中的作用，使用 Aim 2 中的一个或两个都存在缺陷的小鼠模型扩展了这些研究。 Aim 3 在小鼠模型和人类生物样本中部署了 PPARα 和 HNF4α 对 NAFLD 的强大作用。通过比较来表征 PPARα 和 HNF4α 在序列特异性 DNA 结合中的相互作用。近交系小鼠品系中，影响结合基序的自然多态性将揭示选择性和在人类肝脏样本中，PPARα 和 HNF4α 常见的 DNA 结合，我们将检验以下假设： PPARα/HNF4α 基因组结合位点的编码遗传变异是 TG 人群中某些差异的基础水平、NAFLD 以及这些药物对 PPARα 激动剂药物的反应除了这种潜在的临床相关性之外，这些。研究使用创新的基因组和遗传学方法来解决生物学中尚未解答的关键问题 PPARα，包括其与相关核受体的相互作用。