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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。肯尼迪途径，然后经历广泛的脱酰化-反应化重塑通过兰兹循环(非肯尼迪路径)。该反应由溶血磷脂酰胆碱酰基转移酶(LPCAT)催化，该酶在sn-2位添加多不饱和脂肪酸。多不饱和PC含量对血浆的影响膜的结构和功能。到目前为止，已经描述了四种LPCAT亚型，我们确定 LPCAT3是巨噬细胞和脂肪细胞的主要亚型。在这里，我们假设由于Lpcat3缺乏，巨噬细胞质膜中饱和的PC促进通过激活NF-κ-B和MAP-K信号促进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Lpcat3缺乏症可能会钝化胰岛素信号，从而加速炎症、全身性胰岛素抵抗和动脉粥样硬化(目标3)。 Lpcat3的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反临床使用的致动脉粥样硬化策略。