Harnessing macrophage lysosomal lipid metabolism in obesity-associated diseases

利用巨噬细胞溶酶体脂质代谢治疗肥胖相关疾病

基本信息

批准号：
10658896
负责人：
Bettina Mittendorfer
金额：
$ 66.05万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-04 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658896
关键词：
Acid Lipase Adipocytes Adipose tissue Apoptotic Atherosclerosis Attenuated Biogenesis Buffers Catabolism Cells Circulation Complex Cre driver Crowns Data Development Diet Disease Failure Fatty Acids Fatty Liver Fatty acid glycerol esters Fibrosis Functional disorder Gene Cluster Genes Genetic Models Genetic Transcription Goals Hepatocyte High Fat Diet Human Hydrolysis Immune In Vitro Inflammation Inflammatory Ingestion Insulin Resistance Interleukin-1 beta Knockout Mice Kupffer Cells Link Lipids Lipolysis Literature Liver Liver Fibrosis Lysosomes Macrophage Mediating Metabolic Metabolic Diseases Metabolic Pathway Metabolic dysfunction Metabolism Mitochondria Modeling Morbidity - disease rate Mus Nature Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Obesity associated disease Pathogenesis Pathogenicity Pathway interactions Persons Phagocytes Phenotype Plasma Play Population Proteins Publications Publishing Role Signal Transduction Steatohepatitis Structure System TNF gene TREM2 gene Testing Tissues Triglycerides Up-Regulation Work cytokine diet-induced obesity exosome fatty acid metabolism fatty acid oxidation fatty liver disease gene network glucose tolerance immune activation improved in vivo insight insulin tolerance lipid metabolism lipid transport lysosomal proteins medical complication monocyte mortality non-alcoholic fatty liver disease novel strategies obese person obesity treatment overexpression oxidation prevent programs recruit response transcription factor transcriptome sequencing

项目摘要

Project Summary / Abstract Obesity-related metabolic disorders, including insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease, are thought to be caused by low-grade non-infectious inflammation as a result of lipid-mediated immune cell activation, particularly macrophages. However, it has become clear that focusing on macrophage inflammatory signaling is overly simplistic and fails to explain the complex relationship between increased immune cell recruitment to metabolic tissues and disease pathogenesis. Phenotyping of macrophages in adipose tissue and liver demonstrates induction of a lysosomal lipid metabolism program in diet-induced obesity, suggesting that macrophage recruitment to lipid-overloaded tissues might be compensatory in nature. If so, then enhancing a cell-intrinsic program of lipid hydrolysis and metabolism in macrophages should have beneficial metabolic effects. In preliminary work, we show that overexpression of macrophage TFEB, a master transcriptional regulator of lysosomal and fatty acid oxidation genes, enhances the ability of macrophages to metabolize lipids in vitro and ameliorates diet-induced metabolic dysfunction in vivo, presumably because of reduced fatty acid release from adipose tissue. In this proposal, we will investigate the consequences and mechanisms by which activating macrophage lysosomal lipid metabolism in distinct macrophage subsets impacts obesity-induced metabolic dysfunction and fatty liver disease. In Aim-1, we will explore the role of TFEB in adipose tissue macrophages (ATM) in regulating adipose tissue and systemic metabolic function in obesity. This includes assessing TFEB’s effects on the metabolic handling of lipid-rich exosomes and dying adipocytes found in crown-like structures. Our findings in mice will also be confirmed in a human population where we will determine if increased lysosomal lipid metabolism in ATM associates with metabolically normal or metabolically abnormal obesity. In Aim-2, we will utilize unique genetic models to determine the impact of TFEB in liver resident Kupffer cells vs. recruited monocyte-derived macrophages on diet-induced steatosis and fibrosis. Taken together, this proposal will test the hypothesis that induction of a macrophage lysosomal lipid degradation- mitochondrial fatty acid oxidation gene network via TFEB will enhance macrophage lipid handling and could be leveraged to treat obesity-associated insulin resistance and fatty liver disease.

项目概要/摘要肥胖相关的代谢紊乱，包括胰岛素抵抗、2 型糖尿病和非酒精性脂肪肝疾病，被认为是由脂质介导的免疫导致的低度非感染性炎症引起的细胞激活，特别是巨噬细胞然而，很明显，重点关注巨噬细胞。炎症信号传导过于简单化，无法解释炎症信号增加之间的复杂关系免疫细胞募集到代谢组织和脂肪中巨噬细胞的表型。组织和肝脏证明在饮食引起的肥胖中诱导溶酶体脂质代谢程序，表明巨噬细胞招募到脂质超载的组织可能本质上是补偿性的如果是这样，那么。增强巨噬细胞中脂质水解和代谢的细胞内在程序应该具有在前期工作中，我们表明巨噬细胞 TFEB 的过度表达是一个主要因素。溶酶体和脂肪酸氧化基因的转录调节因子，增强巨噬细胞的能力在体外代谢脂质并改善饮食引起的体内代谢功能障碍，可能是因为在本提案中，我们将研究减少脂肪组织中脂肪酸的释放。激活不同巨噬细胞亚群中巨噬细胞溶酶体脂质代谢的机制影响肥胖引起的代谢功能障碍和脂肪肝疾病在 Aim-1 中，我们将探讨 TFEB 的作用。脂肪组织巨噬细胞 (ATM) 调节肥胖中的脂肪组织和全身代谢功能。这包括评估 TFEB 对富含脂质的外泌体和垂死脂肪细胞的代谢处理的影响我们在小鼠中发现的冠状结构也将在人类中得到证实。确定 ATM 中溶酶体脂质代谢增加是否与代谢正常或代谢相关在 Aim-2 中，我们将利用独特的遗传模型来确定 TFEB 对肝脏的影响。驻留库普弗细胞与招募的单核细胞衍生巨噬细胞对饮食诱导的脂肪变性和纤维化的影响。总之，该提案将检验以下假设：诱导巨噬细胞溶酶体脂质降解- 通过 TFEB 的线粒体脂肪酸氧化基因网络将增强巨噬细胞脂质处理和可用于治疗与肥胖相关的胰岛素抵抗和脂肪肝疾病。