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The Role of Sortilin in the Regulation of Apolipoprotein B Secretion from the liver and heart

分拣蛋白在调节肝脏和心脏载脂蛋白 B 分泌中的作用

基本信息

批准号：
9329077
负责人：
Donna M Conlon
金额：
$ 5.71万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9329077
关键词：
Address Adverse effects Alpha Cell Apolipoproteins B Apoptosis Autophagocytosis Beta Particle Biological Blood Circulation Blood Vessels Cardiac Cardiac Myocytes Cause of Death Cholesterol Complex Coronary Arteriosclerosis Disease Disease Progression Dyslipidemias Endoplasmic Reticulum Etiology Fatty Acids Fatty Liver Fellowship Fibrosis Genes Genomics Goals Golgi Apparatus Health Heart Heart failure Hepatic Hepatocyte High Fat Diet Human Impairment In Vitro Insulin Resistance Knock-out Knockout Mice LDL Cholesterol Lipoproteins Laboratories Lead Ligands Lipids Lipoproteins Liver Low-Density Lipoproteins Lysosomes Mediating Mentors Messenger RNA Metabolic Diseases Metabolism Modeling Molecular Monitor Morbidity - disease rate Mus Myocardial dysfunction Non-Insulin-Dependent Diabetes Mellitus Pathologic Pathology Pathway interactions Patients Peripheral Pharmaceutical Preparations Physiological Physiology Plasma Post-Transcriptional Regulation Post-Translational Regulation Proteins Proteolysis Regulation Regulation of Proteolysis Regulatory Pathway Research Personnel Residual state Risk Risk Factors Role Signal Pathway Signal Transduction Societies Sorting - Cell Movement Stress Techniques Testing Therapeutic Therapeutic Intervention Time Tissues Training Transgenic Mice Triglycerides Very low density lipoprotein Wild Type Mouse burden of illness cardiometabolic risk cardiovascular disorder risk career combat density diabetic disorder risk fatty acid oxidation genetic approach genome wide association study genome-wide improved in vivo induced pluripotent stem cell inhibitor/antagonist novel nutrition particle protective effect receptor response sortilin stressor trait

项目摘要

PROJECT SUMMARY Cardiometabolic diseases including coronary artery disease (CAD) and type 2 diabetes (T2D) are major causes of death and morbidity in all societies. These and other metabolic diseases have common etiological insults, including dyslipidemia, the pathological elevation of triglyceride-rich lipoproteins (TRLs) and low-density lipoprotein cholesterol (LDL-C), and treating these risk factors has been shown to reduce disease burden and progression. While statins effectively lower LDL-C, many people are intolerant to their adverse effects and these drugs may not address the residual vascular risk conferred by other proatherogenic lipoproteins such as TRLs, including very low density lipoproteins (VLDLs). VLDLs are precursors to LDL that are synthesized and secreted from the liver to provide triglycerides to peripheral tissues, and thus one underexplored potential avenue for reducing TRL-mediated dyslipidemia is to curb hepatic VLDL secretion. The regulation of VLDL secretion is complex and incompletely understood. Apolipoprotein B (apoB), the key protein component of VLDL, is synthesized in the hepatocyte under tight post-transcriptional control by multiple regulatory pathways, and secreted from the hepatocyte into the circulation to provide nutrition in the form of triglycerides to peripheral tissues. The precise coordination of the pathways governing the fate of apoB as matures into secreted VLDL particles, especially in post-endoplasmic reticulum compartments, is poorly known. A novel gene arising from genome-wide association studies (GWAS) for plasma lipid traits is the SORT1 gene, encoding sortilin, a ubiquitously expressed multi-ligand sorting receptor. Our laboratory previously established SORT1 as the causal gene at the genomic locus associated with plasma cholesterol and CAD and demonstrated that sortilin negatively regulates VLDL-apoB secretion. However, the detailed molecular mechanisms underlying sortilin’s regulation of apoB metabolism and VLDL secretion remain unknown. The precise understanding of how sortilin regulates lipoprotein metabolism and cardiometabolic risk may have important therapeutic implications. The goal of this fellowship proposal is thus to fully elucidate the mechanisms and coordination of VLDL-apoB metabolism by sortilin in the liver and the heart. Specifically, Dr. Conlon will investigate the hypothesis that hepatic sortilin regulates the post-ER fate of apoB for degradation and export to combat lipid overload and secretory stress and that sortilin functions to coordinate intracellular apoB metabolism in response to the number and quality of apoB particles that reach the Golgi and the level of post-ER pre-secretory proteolysis (PERPP) activity. To test this hypothesis, Sort1 liver specific knockout mice and in vitro hepatocyte models will be utilized in the presence of various stressors. Additionally, she will explore how apoB secretion might protect cardiomyocytes from lipotoxicity and the role of sortilin in regulating cardiac apoB secretion. This proposal also aims train Dr. Conlon in new techniques and provide mentoring to allow her to transition into an independent investigator with a career in academics.

项目总结