Project 3: Lipolysis regulation and diabetes-impaired regression

项目 3：脂肪分解调节和糖尿病受损回归

• 批准号: 10450863
• 负责人: Ira J Goldberg
• 金额: $ 49.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450863
• 关键词: ANGPTL4 gene; Adipose tissue; Affect; Angiopoietins; Animal Model; Animals; Antisense Oligonucleotides; Aorta; Apolipoproteins; Arterial Fatty Streak; Arteries; Atherosclerosis; Biology; Blood Vessels; Bone Marrow Transplantation; Cardiovascular Diseases; Cells; Characteristics; Cholesterol; Data; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Diet; Dyslipidemias; Eicosapentaenoic Acid; Endothelial Cells; Fasting; Fatty acid glycerol esters; Fibrates; Foam Cells; Gene Expression; Generations; Genes; Glucose; High Density Lipoproteins; High Fat Diet; Human; Hyperglycemia; Hyperlipidemia; Hypertriglyceridemia; Impairment; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Investigation; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Lesion; Leukocytes; Lipids; Lipolysis; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Meta-Analysis; Methods; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Omega-3 Fatty Acids; Pathogenesis; Patients; Plasma; Process; Proteins; Regulation; Role; Smooth Muscle Myocytes; Sodium; Sorting - Cell Movement; Source; Streptozocin; Subgroup; Sucrose; Testing; Toxic effect; Triglyceride Metabolism; Triglycerides; Vascular Diseases; atherogenesis; cardiovascular disorder risk; feeding; genome wide association study; human data; hypercholesterolemia; inhibitor; insulin sensitivity; interest; islet; laser capture microdissection; lipoprotein lipase; lipoprotein lipase inhibitor; macrophage; magnetic beads; monocyte; novel; particle; prevent; programs; repaired; single-cell RNA sequencing; symporter; transcriptomics; type I and type II diabetes

Diabetes is associated with greater cardiovascular disease (CVD), likely due at least in part to increased circulating levels of atherogenic lipoproteins. The most common dyslipidemia in patients with diabetes, especially Type 2 diabetes, is hypertriglyceridemia (hyperTG). Moreover, recent human data also implicate genes associated with hyperTG such as lipoprotein lipase (LPL), apolipoprotein C3 (APOC3), and angiopoietin-like protein (ANGPTL)3 with CVD. Despite more than 4 decades of investigation, a mechanistic understanding of the relationship of hyperTG and CVD has not been clearly defined. Project 3 of this Program Project proposes to develop and use new animal models to assess how hyperTG and diabetes interact to alter vascular pathobiology. Our studies will focus on changes in arterial LPL using models that increase and decrease lipolysis within and likely along the arterial wall. Monocyte/macrophages are the only white blood cells that highly express LPL and they are the primary source of vascular LPL. Using single cell RNA sequencing, we have found that arterial macrophages have a cluster of high LPL expressing cells and our studies will uncover how LPL itself and LPL in the presence of hyperTG and diabetes alter cells in this and the other clusters. This Project has two specific aims. Aim 1 will determine how hyperTG and local lipolysis affect vascular disease. To do this, we will transplant bone marrow from mice that have an inducible deletion of either LPL (to reduce lipolysis) or ANGPTL4 (to increased LPL activity) into animals that have either normal or increased circulating levels of triglyceride (TGs) due to induced global deletion of LPL. Both atherogenesis and regression will be studied using a novel method we developed to delete and then replenish LDL receptors. In addition, we will test whether changing the composition of circulating TGs by feeding mice an omega 3 fatty acid-rich diet, recently shown to reduce CVD risk, will modify the vascular effects of altering macrophage LPL expression or levels of remnant lipoprotein particles. Aim 2 will test how changes in hyperglycemia/insulin actions and altered lipolysis products affect atherosclerosis regression, endothelial cell lipid accumulation and gene expression. We will create models with insulin deficiency and defective insulin sensitivity due to high fat diets. We were the first to show that defective regression is a robust vascular disease manifestation of diabetes. These studies will involve extensive interactions with the other projects of this Program and use of Cores B and C.

糖尿病与更大的心血管疾病（CVD）有关，可能至少部分是由于增加