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，在细胞内从头合成 Kennedy 途径，然后通过 Lands 循环（非- 肯尼迪途径）再酰化是由溶血磷脂酰胆碱酰基转移酶（LPCAT）催化的。在 sn-2 位添加多不饱和脂肪酸会影响血浆。迄今为止，我们已经描述了四种 LPCAT 亚型。 LPCAT3 是巨噬细胞和脂肪细胞中的主要亚型，我们努力解决这一问题。由于 Lpcat3 缺乏，巨噬细胞质膜中的 PC 饱和，促进通过激活 NFκB 和 MAP 激酶信号传导来抑制炎症并促进炎症诱导全身胰岛素抵抗和动脉粥样硬化（目标 1 和 2）脂肪细胞中的 Lpcat3 缺乏可能会减弱。胰岛素信号传导，从而加速炎症、全身胰岛素抵抗和动脉粥样硬化（目标 3）。 Lpcat3 过度表达应该会产生相反的效果，这项研究的结果可能会导致一种新的抗-Lpcat3 的产生。临床使用的致动脉粥样硬化策略。