The Role of ERRa in liver lipid dysfunction and pathology

ERRa 在肝脂质功能障碍和病理学中的作用

• 批准号: 10345454
• 负责人: Bangyan Stiles
• 金额: $ 36.3万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345454
• 关键词: Address; Alcohol consumption; Alcoholic steatohepatitis; Alcohols; Anabolism; Binding; Bioenergetics; Biogenesis; Biology; CREB1 gene; Cell physiology; ChIP-seq; Chromatin; Chronic; Cirrhosis; Citric Acid Cycle; Complex; Development; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Enzymes; Estrogens; Ethanol; Exhibits; Fatty Acids; Fatty Liver; Fibrosis; Functional disorder; Gene Expression Regulation; General Population; Genes; Genetic Models; Genetic Transcription; Glucose; Goals; Heavy Drinking; High Fat Diet; In Vitro; Individual; Inflammation; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Lipids; Liver; Liver diseases; Malignant neoplasm of liver; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Modification; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Orphan Receptor; Nuclear Receptors; Nylons; Obesity; Oxidative Phosphorylation; PI3K/AKT; Pathology; Patients; Phosphorylation; Physiological; Play; Population; Precipitation; Production; Property; Protein Isoforms; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Receptor Inhibition; Regulation; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Steatohepatitis; System; Testing; Therapeutic Effect; Transcriptional Regulation; Translations; Triglycerides; United States; Up-Regulation; base; design; diet-induced obesity; drinking behavior; estrogen-related receptor; fatty liver disease; feeding; functional outcomes; gain of function; in vivo; inhibitor; insulin signaling; lipid biosynthesis; lipid metabolism; lipidomics; liver injury; liver transplantation; member; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obese person; oxidation; oxidized lipid; particle; patient subsets; promoter; small molecule; small molecule inhibitor; therapeutic evaluation; transcription factor; transcriptome sequencing

Estrogen-related receptor (ERR) plays critical roles in the transcriptional regulation of genes involved in mitochondrial bioenergetics, TCA cycle, mitochondrial oxidative phosphorylation, and fatty acid β-oxidation. This project intends to discover the roles of ERR as novel transcriptional factor for lipid metabolism its involvement in lipid pathology development in the liver. To address the function of ERR in dyslipidemia, we developed a novel small molecule inhibitor (ERR-PA) that can block the binding of ERRs to the promoters of its target genes. Using this compound in diet and genetic models of liver steatosis (NAFLD/ALD) and steatohepatitis (NASH/ASH), our preliminary studies showed that inhibiting ERR robustly blocks the development of steatosis and reverses the lipid accumulation in models where liver steatosis is induced by diet and ethanol feeding as well as genetic alterations. ERR-PA also significantly reduced the fibrosis and inflammation occurring in established steatohepatitis. Using these in vivo as well as in vitro systems, we will explore the molecular mechanisms by which ERR inhibition suppresses the progression of liver disease. The hypothesis to be tested is that ERRs positively regulate transcription of genes encoding enzymes for anabolic lipid metabolism and inhibiting this action blocks steatosis and associated inflammation and fibrosis in NASH/ASH. We will address this hypothesis with the following three aims. Aim1 will investigate the regulation of lipid metabolism via the transcriptional activity of ERRs. This aim will explore the transcriptional complex by which ERRα regulates de novo lipogenesis, glycerolipid biosynthesis and fatty acid β-oxidation. Aim2 will explore the regulation of ERRs by insulin signaling based on our previous discover that ERRα is a downstream target of insulin/PI3K/AKT signaling signal regulated via AKT phosphorylation on CREB and upregulation of PGC-1α. Aim3 will determine the effect of ERR inhibition on oxidative lipid damage in during ASH/NASH development. This aim will investigate lipid, oxidized lipid and other derivatives, ROS production and their contribution to liver damage. The proposed project will explore ERRα as a potential target for inhibiting and reversing fatty liver diseases. The mechanistic and translations approaches will uncover novel biology for lipid metabolism as well as test the therapeutic effect of a small molecule polyamide.

雌激素相关受体（ERR）在基因转录调控中起重要作用 参与线粒体生物能量学、TCA循环、线粒体氧化磷酸化， 脂肪酸β-氧化。本项目旨在发现ERR作为一种新的转录调控因子的作用， 脂质代谢因子参与肝脏脂质病理学发展。解决 为了研究ERR在血脂异常中的作用，我们开发了一种新的小分子抑制剂（ERR-PA）， 可以阻断ERRs与其靶基因启动子的结合。在饮食中使用这种化合物 和肝脏脂肪变性（NAFLD/ALD）和脂肪性肝炎（NASH/ASH）的遗传模型，我们 初步研究表明，抑制ERR可有力地阻断脂肪变性的发展， 逆转由饮食和乙醇诱导的肝脏脂肪变性模型中的脂质蓄积 喂养和基因改变。ERR-PA还显著减少了纤维化， 脂肪性肝炎的炎症。在体内和体外使用这些 系统，我们将探讨ERR抑制抑制的分子机制， 肝病的进展。有待检验的假设是，错误反应正调控 转录编码合成代谢脂质代谢酶的基因并抑制该作用 阻断NASH/ASH中的脂肪变性及相关炎症和纤维化。我们将解决这个问题 假设有以下三个目标。Aim 1将研究脂质代谢的调节 通过ERRs的转录活性。这一目标将探索转录复合体， ERRα调节从头脂肪生成、甘油脂生物合成和脂肪酸β-氧化。AIM2 基于我们先前发现的ERRα，我们将探讨胰岛素信号对ERR的调控。 是通过AKT磷酸化调节的胰岛素/PI 3 K/AKT信号转导的下游靶点 CREB和PGC-1α表达上调。Aim 3将确定ERR抑制对 在ASH/NASH发展过程中的氧化脂质损伤。这一目的将研究脂质，氧化 脂质和其他衍生物、ROS产生及其对肝损伤的贡献。拟议 该项目将探索ERRα作为抑制和逆转脂肪肝疾病的潜在靶点。的 机械和翻译方法也将揭示脂质代谢的新生物学 作为测试小分子聚酰胺的治疗效果。