Novel Role of Bscl2 in Cardiac Substrate Metabolism and Function

Bscl2 在心脏底物代谢和功能中的新作用

基本信息

批准号：
10737113
负责人：
Weiqin Chen
金额：
$ 56.19万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737113
关键词：
Address Adipose tissue Adult Age BSCL2 gene Binding Biochemical Bioenergetics Biogenesis Biological Biological Assay Carboxylesterase 1 Cardiac Cardiac Myocytes Cardiomyopathies Catabolism Cause of Death Cells Clinical Couples Coupling Data Deposition Diabetes Mellitus Diabetic mouse Diet Endoplasmic Reticulum Energy consumption Energy-Generating Resources Essential Fatty Acids Fatty acid glycerol esters Functional disorder Genes Genetic Grant Heart Heart failure Hela Cells Homeostasis Human Hydrolase Hydrolysis Image In Vitro Ion Transport Knock-in Knock-in Mouse Knock-out Lactamase Ligation Link Lipase Lipids Lipodystrophy Lipolysis Mediating Membrane Metabolic Metabolism Mitochondria Mitochondrial Proteins Modeling Molecular Morbidity - disease rate Mus Myocardial Myocardial dysfunction Neonatal Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Patients Physiological Prevalence Process Production Proteins Proteomics Rattus Research Role Site Sucrose System Testing Therapeutic Triglyceride Metabolism Triglycerides carboxylesterase disability fatty acid oxidation heart function insight knock-down lipid metabolism mitochondrial dysfunction mitochondrial metabolism mortality novel novel therapeutic intervention overexpression prevent reconstitution transcriptomic profiling

项目摘要

Project Summary Metabolic perturbations underpin a wide variety of cardiomyopathies. Currently, there are no specific treatments for preventing the onset or progression of cardiomyopathies to heart failure, one of the leading causes of death and disability worldwide. BSCL2/Seipin is a highly conserved endoplasmic reticulum (ER) protein widely implicated in lipid droplet biogenesis and triglyceride (TG) metabolism. However, the molecular machinery responsible for BSCL2-regulated cardiac lipid metabolism has not been elucidated. This grant addresses novel linkages between BSCL2, TG lipolysis, and mitochondrial function in the heart. We found that cardiac BSCL2 deletion elevates adipose triglyceride lipase (ATGL) expression and fatty acid (FA) oxidation, and causes TG reduction and mild cardiac dysfunction with age. However, BSCL2 deletion completely rescues lethal metabolic cardiomyopathy in ATGL-deficient mice. This was achieved by restoring cardiac TG lipolysis and FA oxidation, suggesting the presence of other non-ATGL TG lipase (s)/players downstream of BSCL2. We further employed Bscl2 knock-in mouse and proteomics and showed that BSCL2 interacts with mitochondrial protein and co- fractionates with proteins present in ER membranes associated with mitochondria (MAM). We, therefore, hypothesize that BSCL2 mediates ATGL-independent TG catabolism, ER-mitochondria coupling, and mitochondrial function thus cardiac homeostasis and lipotoxic cardiomyopathy. Aim 1 will elucidate the importance and mechanisms of a novel TG lipase in the heart that controls cardiac triglyceride hydrolysis and FA oxidation downstream of BSCL2. Aim 2 will define whether BSCL2 interacts with a specific mitochondrial protein at ER/mitochondria contact sites to mediate mitochondrial function and lipotoxic cardiomyopathy. This study is highly significant as it defines the novel components and molecular machinery of BSCL2-mediated ATGL-independent pathways that regulate cardiac TG metabolism, MAM, mitochondrial metabolism, and heart function, which can potentially lay an intellectual groundwork for novel therapeutic approaches to metabolic cardiomyopathy.

项目摘要代谢扰动基于各种心肌病。目前，没有具体的治疗为了防止心肌病的发作或进展，死亡的主要原因之一和全世界的残疾。 BSCL2/SEIPIN是一种高度保守的内质网（ER）蛋白与脂质液滴生物发生和甘油三酸酯（TG）代谢有关。但是，分子机械尚未阐明负责BSCL2调节的心脏脂质代谢。这项赠款解决了小说心脏中BSCL2，TG脂解和线粒体功能之间的联系。我们发现心脏BSCL2 缺失升高脂肪甘油三酸酯脂肪酶（ATGL）表达和脂肪酸（FA）氧化，并引起TG 随着年龄的增长和轻度心脏功能障碍。但是，BSCL2删除完全挽救致命的代谢 ATGL缺陷小鼠的心肌病。这是通过恢复心脏TG脂解和FA氧化来实现的，表明存在BSCL2下游的其他非ATGL TG脂肪酶/玩家。我们进一步雇用 BSCL2敲入小鼠和蛋白质组学，表明BSCL2与线粒体蛋白和共同与线粒体（MAM）相关的ER膜中存在的蛋白质分数。因此，我们假设BSCL2介导了无关ATGL的TG分解代谢，ER-线粒体偶联和线粒体功能因此心脏稳态和脂肪毒性心肌病。 AIM 1将阐明心脏中新型TG脂肪酶的重要性和机制控制心脏甘油三酸酯水解和 BSCL2下游的FA氧化。 AIM 2将定义BSCL2是否与特定线粒体相互作用 ER/线粒体接触位点的蛋白质介导线粒体功能和脂肪毒性心肌病。这研究非常重要，因为它定义了BSCL2介导的新成分和分子机制不依赖ATGL的途径，该途径调节心脏TG代谢，MAM，线粒体代谢和心脏功能，这可能为新型治疗方法提供新的智力基础心肌病。