Adipose MTP and FIT2 in the regulation of plasma lipids, obesity and atherosclerosis

脂肪MTP和FIT2在血脂、肥胖和动脉粥样硬化调节中的作用

• 批准号: 10628990
• 负责人: M Mahmood Hussain
• 金额: $ 64.34万
• 依托单位: NYU LONG ISLAND SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628990
• 关键词: Ablation; Adipocytes; Adipose tissue; Affect; Anti-Inflammatory Agents; Apolipoproteins B; Atherosclerosis; Binding; Binding Proteins; Biogenesis; Bioinformatics; Biology; Biometry; Blood; Blood Vessels; Body Weight decreased; Cardiovascular Diseases; Catabolism; Cause of Death; Cells; Cholesterol; Collaborations; Cytosol; Deposition; Endoplasmic Reticulum; Endothelial Cells; Energy Metabolism; Fatty Liver; Fatty acid glycerol esters; Genes; Heart Diseases; Hepatic; Human; Hydrolysis; Hypertriglyceridemia; Inflammation; Inflammatory; Inflammatory Response; Integral Membrane Protein; Knock-out; Link; Lipase; Lipids; Lipolysis; Lipoproteins; Liver; Macrophage; Measures; Membrane; Metabolism; Monitor; Mus; Obesity; Pathogenicity; Pathology; Phenotype; Plasma; Production; Protein Deficiency; Proteins; Proteomics; RNA analysis; Regulation; Resistance; Role; Route; Sampling; Site; Testing; Translating; Triglycerides; Very low density lipoprotein; Weight Gain; Work; adipocyte biology; biological adaptation to stress; cardiovascular risk factor; cytokine; diet-induced obesity; druggable target; innovation; insight; lipid metabolism; lipidomics; microsomal triglyceride transfer protein; mouse model; novel; obese patients; oxidation; protein function; single-cell RNA sequencing; tool; transcriptome sequencing; uptake

ABSTRACT – PROJECT 1: High blood levels of apoB-containing lipoproteins (apoB-Lps) are risk factors for cardiovascular diseases. ApoB-Lp production requires microsomal triglyceride (TG) transfer protein (MTP). However, MTP’s role in adipose tissue, which does not produce apoB-Lps, is unknown. Fat storage-inducing transmembrane protein 2 (FIT2) is another TG-binding protein that is involved in lipid droplet (LD) formation in adipose tissue. While MTP functions in lumen of the endoplasmic reticulum (ER), FIT2 assists in the budding of LDs from the ER membrane towards cytosol. We hypothesize that these two TG binding proteins perform different functions that affect adipocyte biology, hepatic lipid metabolism, and atherosclerosis. We showed that adipose-specific MTP deficient (A-Mttp−/−) mice are resistant to diet- induced obesity, hepatosteatosis and atherosclerosis, but adipose FIT2 deficiency causes hepatosteatosis and inflammation. These contrasting phenotypes compel us to ask if MTP deficiency can ameliorate pathologies associated with FIT2 deficiency. Aim 1.1: Role of adipose MTP in hypertriglyceridemia, hepatosteatosis, and atherosclerosis. We showed that adipose MTP inhibits adipose TG lipase (ATGL). We will: 1) ask if adipose MTP also modulates other lipases beyond ATGL; 2) work with P2 and P3 to elucidate mechanisms for hypertriglyceridemia and reduced hepatosteatosis; and 3) collaborate with C1–C3 to explain why atherosclerosis is lower in A-Mttp−/− mice. These studies will uncover how MTP promotes adipose TG storage and obesity. We propose that inhibiting adipose-specific MTP function will reduce obesity and atherosclerosis. Aim 1.2: Role of MTP and FIT2 in adipose biology, hepatosteatosis, and atherosclerosis. Given the distinct roles and sites of action of MTP and FIT2 within adipocytes, we will study the effect of adipose-specific MTP and FIT2 deficiencies on whole-body metabolism, adipose lipolysis, and atherosclerosis, and ask if MTP deficiency ameliorates FIT2-associated pathology with help from C1–C3 and expertise from P2 and P3. Our studies will: 1) provide novel information on the roles of adipose MTP and FIT2 in adipose, liver, and vascular biology; 2) generate novel mouse models; 3) explain roles of MTP and FIT2 in metabolism, TG hydrolysis, and FA secretion and oxidation; and 4) define how adipose–liver crosstalk controls obesity, hypertriglyceridemia, hepatosteatosis, and atherosclerosis. Elucidating the mechanisms of apoB-Lps production depends on collaboration with P2. We will then work with P3 to: 1) study intravascular catabolism of apoB-Lps produced by adipose–specific MTP- and FIT2-deficient mice, 2) monitor apoB-Lp uptake by endothelial cells, and 3) elucidate pro- or anti-inflammatory responses in adipocytes and macrophages. Bioinformatics analyses of RNA-seq and single cell RNA-seq (by C1), Lp characterization (by C2), and atherosclerosis studies (by C3) will yield novel insights into how adipose-specific proteins regulate metabolism.

摘要-项目1：高水平的含载脂蛋白B的脂蛋白（apoB-Lps）是危险因素 治疗心血管疾病ApoB-Lp的产生需要微粒体甘油三酯（TG）转移蛋白（MTP）。 然而，MTP在不产生apoB-Lps的脂肪组织中的作用尚不清楚。脂肪储存诱导 跨膜蛋白2（FIT 2）是另一种TG结合蛋白，其参与脂滴（LD）的形成， 脂肪组织MTP在内质网（ER）腔中发挥作用，而FIT 2则协助出芽 从内质网膜到胞质溶胶的LDs。我们假设这两种TG结合蛋白 执行影响脂肪细胞生物学、肝脏脂质代谢的不同功能， 动脉粥样硬化我们发现，脂肪特异性MTP缺陷（A-Mttp−/−）小鼠对饮食有抵抗力， 诱导肥胖、脂肪肝和动脉粥样硬化，但脂肪FIT 2缺乏导致脂肪肝 和炎症。这些对比鲜明的表型迫使我们问MTP缺乏是否可以改善 与FIT 2缺陷相关的病理学。 目的1.1：脂肪MTP在高脂血症、脂肪肝和动脉粥样硬化中的作用。我们 显示脂肪MTP抑制脂肪TG脂肪酶（ATGL）。我们将：1）询问脂肪MTP是否也调节 ATGL以外的其他脂肪酶; 2）与P2和P3一起工作，以阐明高胆固醇血症的机制， 减少肝脂肪变性; 3）与C1-C3合作解释为什么动脉粥样硬化在A-Mttp−/−中较低 小鼠这些研究将揭示MTP如何促进脂肪TG储存和肥胖。我们建议 抑制脂肪特异性MTP功能将减少肥胖和动脉粥样硬化。 目的1.2：MTP和FIT 2在脂肪生物学、脂肪肝和动脉粥样硬化中的作用。鉴于 不同的作用和MTP和FIT 2在脂肪细胞内的作用位点，我们将研究脂肪特异性 MTP和FIT 2缺乏对全身代谢、脂肪分解和动脉粥样硬化的影响，并询问MTP是否 在C1-C3的帮助下以及来自P2和P3的专业知识的帮助下，FIT 2缺乏改善了FIT 2相关的病理学。 我们的研究将：1）提供关于脂肪MTP和FIT 2在脂肪、肝脏和肝脏中作用的新信息， 血管生物学; 2）产生新的小鼠模型; 3）解释MTP和FIT 2在代谢、TG 水解和FA分泌和氧化;以及4）定义脂肪-肝脏串扰如何控制肥胖， 高脂血症、脂肪肝和动脉粥样硬化。apoB-Lps作用机制的探讨 生产取决于与P2的合作。然后，我们将与P3一起工作：1）研究血管内钙化， 由脂肪特异性MTP和FIT 2缺陷小鼠产生的apoB-Lp，2）监测apoB-Lp的摄取， 内皮细胞，和3）阐明脂肪细胞和巨噬细胞中的促炎或抗炎反应。 RNA-seq和单细胞RNA-seq的生物信息学分析（通过C1）、Lp表征（通过C2）和 动脉粥样硬化研究（C3）将产生新的见解，脂肪特异性蛋白质如何调节代谢。