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: 10531889
• 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/10531889
• 关键词: Address; Alcohol consumption; Alcoholic Liver Diseases; 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; 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 dysfunction; 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; Triglycerides; United States; Up-Regulation; design; diet-induced obesity; drinking behavior; estrogen-related receptor; fatty liver disease; feeding; functional outcomes; gain of function; glucose metabolism; in vivo; inhibitor; insulin signaling; lipid biosynthesis; lipid metabolism; lipidomics; liver injury; liver transplantation; loss of function; 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; translational approach

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)在基因转录调控中发挥重要作用 参与线粒体生物能量学，TCA循环，线粒体氧化磷酸化，以及 脂肪酸β氧化。本项目旨在发现ERR作为新的转录的作用 脂代谢因子，参与肝脏中脂类的病理发展。致信地址 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)，它可以 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，我们的 初步研究表明，抑制ERR有力地阻止了脂肪变性的发展和 逆转饮食和酒精诱导的肝脏脂肪变性模型中的脂质堆积 进食和基因改变。ERR-PA还显著减少了纤维化和 在已确诊的脂肪性肝炎中发生的炎症。在体内和体外使用这些化合物 系统中，我们将探索ERR抑制抑制 肝脏疾病的进展。需要检验的假设是错误正向调节 编码合成类脂代谢酶的基因转录和抑制这一作用 阻止NASH/ASH中的脂肪变性和相关的炎症和纤维化。我们将解决这一问题 假设有以下三个目的。AIM1将研究脂代谢的调节 通过ERRS的转录活动。这个目标将探索转录复合体，通过它 ERRα调节新生脂肪生成、甘油脂生物合成和脂肪酸β氧化。AIM2 我将基于我们之前的发现探索胰岛素信号对错误的调节作用，Errα 是胰岛素/PI3K/AKT信号转导信号的下游靶点 CREB与pGC-1α的上调AIM3将确定ERR抑制对 在ASH/NASH发展过程中的氧化脂质损伤。这一目标将研究氧化后的脂质 脂质和其他衍生物、ROS的产生及其对肝脏损害的贡献。建议数 该项目将探索Errα作为抑制和逆转脂肪肝疾病的潜在靶点。这个 机械论和翻译方法也将发现脂代谢的新生物学 作为一种小分子聚酰胺的疗效测试。