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

• 批准号: 10372221
• 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
• 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/10372221
• 关键词: Address; Affect; Agonist; Amino Acids; Atherosclerosis; Binding; Binding Sites; Biology; Cardiometabolic Disease; Cardiovascular system; Cell model; Cessation of life; Choline; 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; 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

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.

项目总结/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）。有复苏 对靶向肝核受体PPARα的药物感兴趣。此类贝特类药物已经用于 高甘油三酯血症，有新的认识，TG独立地引起动脉粥样硬化性心血管疾病 降低TG可降低患病风险。此外，PPAR激动剂可能是第一批药物之一， 批准NAFLD。NAFLD的不良临床结局，如肝功能衰竭、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 出乎意料地显示，PPARα缺乏和PPARα激动剂治疗均不能改变肝脂肪变性， 但显著影响纤维化（分别增加和减少纤维化）。PPARα在肝细胞中的功能是结合 调节DNA，影响脂质代谢关键基因的表达。相关的核受体HNF 4 α是 不是药物靶点，但调节相似的基因并结合相似的调控DNA。我们假设 PPARα和HNF 4 α在DNA结合中的作用影响肝细胞基因调控，与发病机制有关， NAFLD的治疗我们的实验探测全基因组核受体结合位点和基因调控， 在正常和脂肪肝中，基础和对药物的反应。目的1定义了PPARα的相互依赖性 和HNF 4 α在肝脏基因调控中的作用。目标2扩展了这些研究 在小鼠模型和人生物标本中，PPARα和HNF 4 α与NAFLD的关系。Aim 3部署强大的 描述序列特异性DNA结合中PPARα和HNF 4 α相互作用的遗传学工具。通过比较 近交系小鼠品系，影响结合基序的天然多态性将揭示选择性和 通过PPARα和HNF 4 α共同结合DNA。在人类肝脏样本中，我们将检验以下假设： PPARα/HNF 4 α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以及这些对PPARα激动剂药物的反应。除了这种潜在的临床相关性，这些 研究使用创新的基因组和遗传方法来解决生物学中的关键未回答的问题， PPARα，包括其与相关核受体的相互作用。