Effects of PC remodeling on macrophages and adipocytes: its relevance to atherosclerosis

PC 重塑对巨噬细胞和脂肪细胞的影响：其与动脉粥样硬化的相关性

基本信息

批准号：
9914073
负责人：
XIAN-CHENG JIANG
金额：
$ 40.38万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914073
关键词：
1-Phosphatidylinositol 3-Kinase Acyltransferase Adipocytes Adipose tissue Antiatherogenic Arterial Fatty Streak Atherosclerosis Body Weight CD80 gene Caveolae Cell membrane Cells Cellular Structures Chronic Clinical Closure by clamp Coculture Techniques Defect Development Diet Disease Dyslipidemias Fatty Acids Foam Cells Glucose Hematopoietic High Fat Diet ITGAM gene Immune Impairment Infiltration Inflammation Inflammatory Inflammatory Response Insulin Insulin Receptor Insulin Resistance Interleukin-6 Knockout Mice Lead Lecithin Link Lipids Lipolysis Lipopolysaccharides Low Density Lipoprotein Receptor Lysophosphatidylcholines Mediating Membrane Membrane Lipids Membrane Structure and Function Metabolic Metabolic Diseases Mitogen-Activated Protein Kinases Mus Myeloid Cells Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Outcome Study PLA2G6 gene Palmitates Pathology Pathway interactions Peritoneal Phenotype Plasma Polyunsaturated Fatty Acids Positioning Attribute Process Production Protein Family Protein Isoforms Proto-Oncogene Proteins c-akt Reaction Regulation Saturated Fatty Acids Signal Transduction System TLR4 gene TNF gene Testing Triglycerides Visceral base cell type chemokine cytokine deacylation glucose disposal glucose metabolism glucose tolerance glucose uptake inflammatory marker insulin sensitivity insulin signaling insulin tolerance knock-down knockout gene macrophage metabolic phenotype novel overexpression polyunsaturated phosphatidylcholine prevent protein-tyrosine kinase c-src receptor recruit subcutaneous

项目摘要

Phosphatidylcholine (PC) is the major component of cell membranes and is synthesized de novo in the Kennedy pathway and then undergoes extensive deacylation-reacylation remodeling via Lands' cycle (non- Kennedy pathway). The reacylation is catalyzed by lysophosphatidylcholine acyltransferase (LPCAT), which adds a polyunsaturated fatty acid at the sn-2 position. Polyunsaturated PC content influences plasma membrane structure and function. Four LPCAT isoforms have been described to date, and we determined that LPCAT3 is the major isoform in macrophages and adipocytes. Here, we hypothesize that an increase in saturated PCs in the plasma membrane of macrophages, as a consequence of Lpcat3 deficiency, promotes inflammation by activating NFκB and MAP kinase signaling and promotes inflammation-induced systemic insulin resistance and atherosclerosis (Aims 1 and 2). Lpcat3 deficiency in adipocytes might blunt insulin signaling, thereby accelerating inflammation, systemic insulin resistance and atherosclerosis (Aim 3). Lpcat3 overexpression should have the opposite effects. The outcomes of this study could lead to a novel anti- atherogenic strategy for clinical use.

磷脂酰胆碱（PC）是细胞膜的主要成分，在从头合成肯尼迪途径，然后通过陆地周期进行广泛的脱酰化 - 氧化重塑（非 - 肯尼迪途径）。该反应是通过溶血磷脂酰胆碱酰基转移酶（LPCAT）催化的，该胆碱转移酶（LPCAT）在SN-2位置增加了多不饱和脂肪酸。多不饱和PC含量会影响血浆膜结构和功能。迄今已描述了四个LPCAT同工型，我们确定了该LPCAT3是巨噬细胞和脂肪细胞中的主要同工型。在这里，我们假设有所增加由于LPCAT3缺乏，巨噬细胞质膜中的饱和PC促进了通过激活NFκB和MAP激酶信号传导并促进注射诱导的炎症全身性胰岛素抵抗和动脉粥样硬化（目标1和2）。脂肪细胞中的LPCAT3缺乏可能会蓝色胰岛素信号传导，从而加速炎症，全身性胰岛素抵抗和动脉粥样硬化（AIM 3）。 LPCAT3过表达应具有相反的效果。这项研究的结果可能导致一种新颖的抗临床使用的动脉粥样硬化策略。