Targeting the Enterocyte to Prevent Vascular Inflammation

靶向肠上皮细胞预防血管炎症

基本信息

批准号：
10175015
负责人：
Alan M Fogelman
金额：
$ 57.44万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10175015
关键词：
Aorta Apolipoprotein A-I Atherosclerosis Blood Circulation Blood Vessels Brain Cells Cholesterol Chylomicrons Data Diet Dietary Fats Dyslipidemias Encephalitis Endotoxins Enterocytes Event Fatty acid glycerol esters Genes High Density Lipoprotein Cholesterol High Density Lipoproteins Immune Inflammatory Intestinal permeability Intestines Kidney Lead Lipids Lipopolysaccharides Low Density Lipoprotein Receptor Lymphatic Lysophosphatidylcholines Lysophospholipase Mesentery Methods Mus Oleic Acids Oral Oral Administration Organ Oxides Pathway interactions Peptides Plasma Process Proteins Publishing Role Serum Signal Pathway Signaling Molecule Small Intestines Testing Tissues Tomatoes Transgenes Transgenic Organisms Travel Triglycerides Villus Viral absorption desaturase feeding forest host microbiome jejunum knock-down lipidomics lysophosphatidic acid microbiome microbiome alteration microbiome composition mimetics mouse model notch protein oxidation oxidized lipid peptidomimetics preservation prevent response systemic inflammatory response vascular inflammation western diet

项目摘要

Abstract Feeding low density lipoprotein receptor null (Ldlr-/-) mice a Western Diet (WD) not only causes dyslipidemia and atherosclerosis, it also causes vascular inflammation of brain, kidneys, and the small intestine mesentery. The intestine contains more immune cells than any other organ in the body. The number and activation state of these immune cells is in part governed by bacterial and viral products that get past the enterocytes, but they are also governed by lipid signaling molecules such as lysophosphatidic acid 18:1 (LPA 18:1). A major precursor to LPA 18:1 is lysophosphatidylcholine 18:1 (LysoPC 18:1). LysoPC 18:1 is formed in enterocytes preferentially using oleic acid synthesized in the enterocytes by Stearoyl Co-A desaturase-1 (Scd1). Enterocyte LysoPC 18:1 is converted to LPA 18:1 by the action of enterocyte lysophospholipase D (autotaxin). Dietary fat alters the microbiome and increases intestinal permeability via signaling pathways dually controlled by the levels of bacterial lipopolysaccharide (LPS), and enterocyte generated lipid signaling molecules such as LPA 18:1. We hypothesize that the levels of LPS and molecules such as LPA 18:1 in the small intestine determine the systemic response to dietary fat challenge. Aim 1 will determine the role and mechanism(s) of enterocyte Scd1 in diet-induced dyslipidemia and vascular inflammation. Administering LPA 18:1 or LysoPC 18:1 to Ldlr-/- mice on a chow diet mimicked feeding these mice WD. We generated Ldlr-/- mice with enterocyte knockdown of Scd1, which on WD lowered enterocyte levels of LysoPC 18:1 and LPA 18:1. We will determine if enterocyte knockdown of Scd1 favorably alters: 1) aortic atherosclerosis; 2) cholesterol and lipid absorption; 3) composition of the microbiome; 4) microbiome-host interactions; 5) intestinal permeability and serum endotoxin levels; 6) lipids secreted from enterocytes (determined using a lipidomics approach); and 7) Notch pathway to ameliorate diet-induced vascular inflammation. Aim 2 will determine the role and mechanism(s) of enterocyte lysophospholipase D (autotaxin). We generated Ldlr-/- mice with enterocyte knockdown of Enpp2, the gene for autotaxin. Enterocyte knockdown of Enpp2 reduced levels of LPA 18:1 in enterocytes and plasma, and decreased WD-induced dyslipidemia and systemic inflammation. We will determine if enterocyte knockdown of Enpp2 reduces aortic atherosclerosis. We hypothesize that increased levels of enterocyte unsaturated LPA species such as LPA 18:1 lead to the oxidation of chylomicrons secreted from enterocytes, which leads to vascular inflammation. We will determine if enterocyte knockdown of Enpp2 favorably alters these events. Aim 3 will determine the mechanism(s) of action of a concentrate of tomatoes expressing the apoA-I mimetic peptide 6F from a transgene (Tg6F) in ameliorating diet-induced dyslipidemia and vascular inflammation. We will determine if Tg6F mimics enterocyte knockdown of Scd1 and Enpp2. We will determine the lipids removed from mouse jejunum by Tg6F. We will determine if Tg6F preserves the Notch pathway and prevents vascular inflammation in mice fed chow supplemented with LysoPC 18:1, or LPA 18:1 or fed WD.

抽象的喂养低密度脂蛋白受体无效（LDLR - / - ）小鼠西方饮食（WD）不仅引起血脂异常和动脉粥样硬化，它还引起大脑，肾脏和小肠肠系膜的血管炎症。肠中包含的免疫细胞比体内任何其他器官都多。数量和激活状态这些免疫细胞部分受细菌和病毒产物的控制，这些产物经过肠细胞，但它们是还由脂质信号分子（例如溶血磷酸酸18：1）（LPA 18：1）控制。专业 LPA 18：1的前体是溶物磷脂酰胆碱18：1（lysopc 18：1）。 lysopc 18：1在肠细胞中形成优先使用肠烯酰基Co-A去饱和酶-1（SCD1）在肠上皮细胞中合成的油酸。肠肠细胞 lysopc 18：1通过肠植物细胞溶血磷脂酶D（自动肝素）的作用转化为LPA 18：1。饮食脂肪改变微生物组，并通过双方控制的信号通路增加肠道通透性细菌脂多糖（LPS）和肠肠细胞产生的脂质信号分子（如LPA）的水平 18：1。我们假设LPA和分子（例如LPA 18：1）的水平在小肠中确定对饮食脂肪挑战的系统性反应。 AIM 1将确定肠球菌的作用和机制饮食引起的血脂异常和血管炎症中的SCD1。管理LPA 18：1或lysopc 18：1至ldlr - / - 小鼠在食物饮食上模仿了这些小鼠WD。我们用肠球菌敲除生成了ldlr - / - 鼠标 scd1的作品，在wd上降低了肠肠细胞水平18：1和lpa 18：1。我们将确定肠肠细胞是否 SCD1的敲低有利的变化：1）主动脉动脉粥样硬化； 2）胆固醇和脂质吸收； 3）微生物组的组成； 4）微生物组宿主相互作用； 5）肠道通透性和血清内毒素水平； 6）从肠球菌分泌的脂质（使用脂质组学方法确定）； 7）通往改善饮食引起的血管炎症。 AIM 2将确定肠球菌的作用和机制溶物磷脂酶D（自身赛）。我们生成了ldlr - / - 小鼠，用肠球菌敲除eNPP2的基因自动赛。 ENPP2的肠细胞敲低降低了肠细胞和血浆中LPA 18：1的水平，以及 WD诱导的血脂异常和全身性炎症减少。我们将确定肠肠细胞是否 ENPP2减少了主动脉粥样硬化。我们假设肠肠细胞不饱和LPA的水平增加诸如LPA 18：1之类的物种导致肠肠细胞分泌的乳糜微粒的氧化，从而导致血管炎症。我们将确定ENPP2的肠肠细胞是否有利地改变了这些事件。目的 3将确定表达apoa-i模拟的浓缩西红柿的作用机制来自转基因（TG6F）的肽6F在改善饮食引起的血脂异常和血管炎症中。我们将确定TG6F是否模拟SCD1和ENPP2的肠肠细胞敲低。我们将确定去除的脂质来自TG6F的鼠标空肠。我们将确定TG6F是否保留了缺口途径并防止血管喂食的小鼠炎症，补充了lysopc 18：1或LPA 18：1或喂养WD。