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：血液中含 apoB 的脂蛋白 (apoB-Lps) 水平高是危险因素 用于心血管疾病。 ApoB-Lp 的生产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。诱导脂肪储存 跨膜蛋白 2 (FIT2) 是另一种 TG 结合蛋白，参与脂质滴 (LD) 的形成 脂肪组织。 MTP 在内质网 (ER) 腔中发挥作用，而 FIT2 则有助于出芽 LDs 从 ER 膜到细胞质。我们假设这两种 TG 结合蛋白 执行影响脂肪细胞生物学、肝脂质代谢的不同功能，以及 动脉粥样硬化。我们发现脂肪特异性 MTP 缺陷 (A-Mttp−/−) 小鼠对饮食具有抵抗力 诱发肥胖、肝脂肪变性和动脉粥样硬化，但脂肪 FIT2 缺乏会导致肝脂肪变性 和炎症。这些对比鲜明的表型迫使我们思考 MTP 缺乏是否可以改善 与 FIT2 缺陷相关的病理。 目标 1.1：脂肪 MTP 在高甘油三酯血症、肝脂肪变性和动脉粥样硬化中的作用。我们 表明脂肪 MTP 抑制脂肪 TG 脂肪酶 (ATGL)。我们将：1) 询问脂肪 MTP 是否也有调节作用 ATGL 以外的其他脂肪酶； 2) 与 P2 和 P3 合作阐明高甘油三酯血症的机制和 减少肝脂肪变性； 3) 与 C1–C3 合作解释为什么 A-Mttp−/− 中动脉粥样硬化较低 老鼠。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。 目标 1.2：MTP 和 FIT2 在脂肪生物学、肝脂肪变性和动脉粥样硬化中的作用。鉴于 MTP 和 FIT2 在脂肪细胞内的不同作用和作用位点，我们将研究脂肪特异性的作用 MTP和FIT2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 缺乏症在 C1-C3 的帮助以及 P2 和 P3 的专业知识的帮助下改善了 FIT2 相关的病理学。 我们的研究将：1）提供关于脂肪 MTP 和 FIT2 在脂肪、肝脏和脂肪组织中的作用的新信息。 血管生物学； 2）生成新颖的小鼠模型； 3）解释MTP和FIT2在代谢、TG中的作用 水解、FA分泌和氧化； 4) 定义脂肪-肝脏串扰如何控制肥胖， 高甘油三酯血症、肝脂肪变性和动脉粥样硬化。阐明 apoB-Lps 的机制 制作依赖于与P2的合作。然后我们将与 P3 合作：1）研究血管内分解代谢 由脂肪特异性 MTP 和 FIT2 缺陷小鼠产生的 apoB-Lp，2) 通过以下方式监测 apoB-Lp 摄取： 内皮细胞，3) 阐明脂肪细胞和巨噬细胞的促炎或抗炎反应。 RNA-seq 和单细胞 RNA-seq（通过 C1）、Lp 表征（通过 C2）的生物信息学分析，以及 动脉粥样硬化研究（由 C3 进行）将为了解脂肪特异性蛋白质如何调节代谢提供新的见解。