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: 10833730
• 负责人: Bangyan Stiles
• 金额: $ 2.59万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10833730
• 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（Estrogen-related receptor， ERR）在基因转录调控中起着至关重要的作用