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：
9797102
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/9797102
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 Inflammation 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 lysophosphatidic acid microbiome microbiome alteration microbiome composition mimetics mouse model notch protein oxidation oxidized lipid peptidomimetics preservation prevent 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.

抽象的用西方饮食（WD）喂养低密度脂蛋白受体无效（Ldlr-/-）小鼠不仅会导致血脂异常和动脉粥样硬化，它还会引起大脑、肾脏和小肠系膜的血管炎症。肠道比体内任何其他器官含有更多的免疫细胞。数量及激活状态这些免疫细胞部分受到穿过肠上皮细胞的细菌和病毒产物的控制，但它们也受溶血磷脂酸 18:1 (LPA 18:1) 等脂质信号分子控制。一个专业 LPA 18:1 的前体是溶血磷脂酰胆碱 18:1 (LysoPC 18:1)。 LysoPC 18:1 在肠细胞中形成优先使用由硬脂酰辅酶 A 去饱和酶 1 (Scd1) 在肠细胞中合成的油酸。肠上皮细胞 LysoPC 18:1 在肠细胞溶血磷脂酶 D（自分泌运动因子）的作用下转化为 LPA 18:1。膳食脂肪通过由细菌双重控制的信号通路改变微生物组并增加肠道通透性细菌脂多糖 (LPS) 和肠上皮细胞产生的脂质信号分子（如 LPA）的水平 18:1。我们假设小肠中 LPS 和 LPA 18:1 等分子的水平决定了对膳食脂肪挑战的全身反应。目标 1 将确定肠上皮细胞的作用和机制 Scd1 在饮食引起的血脂异常和血管炎症中的作用。将 LPA 18:1 或 LysoPC 18:1 施用至 Ldlr-/- 吃食物的小鼠模仿了WD喂养这些小鼠。我们生成了肠细胞敲低的 Ldlr-/- 小鼠 Scd1，在 WD 上降低了 LysoPC 18:1 和 LPA 18:1 的肠上皮细胞水平。我们将确定肠上皮细胞是否 Scd1 的敲除有利地改变： 1) 主动脉粥样硬化； 2）胆固醇和脂质的吸收； 3）微生物组的组成； 4）微生物组与宿主的相互作用； 5）肠道通透性和血清内毒素级别； 6) 肠细胞分泌的脂质（使用脂质组学方法测定）； 7)Notch途径改善饮食引起的血管炎症。目标 2 将确定肠上皮细胞的作用和机制溶血磷脂酶 D（自分泌运动因子）。我们生成了肠上皮细胞 Enpp2 敲低的 Ldlr-/- 小鼠，Enpp2 是自分泌运动因子。 Enpp2 的肠上皮细胞敲除降低了肠上皮细胞和血浆中 LPA 18:1 的水平，并且减少 WD 引起的血脂异常和全身炎症。我们将确定是否肠细胞敲低 Enpp2 减少主动脉粥样硬化。我们假设肠上皮细胞不饱和 LPA 水平增加 LPA 18:1 等物种会导致肠上皮细胞分泌的乳糜微粒氧化，从而导致血管炎症。我们将确定 Enpp2 的肠上皮细胞敲低是否会有利地改变这些事件。目的 3 将确定表达 apoA-I 模拟物的番茄浓缩物的作用机制来自转基因 (Tg6F) 的肽 6F 可改善饮食引起的血脂异常和血管炎症。我们将确定 Tg6F 是否模拟 Scd1 和 Enpp2 的肠细胞敲低。我们将确定去除的脂质来自小鼠空肠的 Tg6F。我们将确定 Tg6F 是否保留 Notch 通路并防止血管饲喂补充了 LysoPC 18:1 或 LPA 18:1 的食物或饲喂 WD 的小鼠出现炎症。