Intestinal Lipid Processing, Bile Acid Metabolism, and Pancreatic Islet Function

肠道脂质加工、胆汁酸代谢和胰岛功能

基本信息

批准号：
10339427
负责人：
Chi- Liang Eric Yen
金额：
$ 38.21万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-23 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10339427
关键词：
2-acylglycerol O-acyltransferase ASBT protein Acyl Coenzyme A Affect Alpha Cell Antibiotics Apical B-Lymphocytes Beta Cell Bile Acids Cecum Chemicals Communication Development Diabetes Mellitus Diabetic mouse Diet Dietary Fats Digestion Disease Energy Metabolism Environment Enzymes Epidemic Escherichia coli Exhibits Failure Fatty acid glycerol esters GCG gene GLP-I receptor Genes Germ-Free Goals Health Health Care Costs Healthcare Hormones Human Hydrolase Hyperglycemia Insulin Insulin Resistance Intervention Intestines Islets of Langerhans Isotopes Knowledge Life Ligands Link Lipids Macronutrients Nutrition Mediating Membrane Metabolic Metabolic Diseases Metabolism Molecular Morphology Mus Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity Pancreas Pathway interactions Patients Pharmacologic Substance Physiological Plasma Predisposition Prevalence Prevention Process Receptor Signaling Reporting Research Resistance Resources Role Signal Pathway Signal Transduction Societies Sodium Streptozocin Structure of alpha Cell of islet Structure of beta Cell of islet Taurocholic Acid Testing Therapeutic Intervention Tissues Toxin Tracer Triglycerides United States Ursodeoxycholic Acid Wild Type Mouse Work absorption bile acid metabolism bile salts care burden combat endoplasmic reticulum stress energy balance feeding glucagon-like peptide 1 glycemic control gut microbiota improved inhibitor insight insulin secretion islet microbial muricholic acid novel obesity treatment overexpression pancreatic islet function pancreatic juice preservation prevent preventive intervention productivity loss proglucagon protective effect receptor receptor-mediated signaling

项目摘要

The prevalence of diabetes has reached epidemic proportions in the United States, gravely afflicting patients and burdening societies with productivity loss and health care costs. Diabetes is characterized by a reduction in beta cell mass in the pancreas, or a failure of beta cells to secrete enough insulin to fully compensate for insulin resistance. Augmenting or preserving functional beta cell mass is an attractive objective for preventing or treating diabetes; however, we have insufficient intervention targets. The long-term goal of our research is to better understand how intestinal lipid processing controls systemic metabolism and explore intervention targets to combat metabolic diseases. We have reported that acyl CoA:monoacylglycerol acyltransferase 2 (MGAT2) mediates intestinal fat absorption and regulates systemic energy balance. Although mice lacking a functional MGAT2 gene (Mogat2–/–) or lacking MGAT2 specifically in the intestine absorb normal amounts of dietary fat, they exhibit delayed fat absorption, increased energy expenditure, and resistance to obesity and related disorders. Intriguingly, we found that loss of MGAT2 protects mice against chemically- and genetically-induced diabetes by preserving functional beta cell mass. Associated with the protection, Mogat2–/– mice have increased plasma bile acids, known to have potent metabolic effects as ligands for membrane and nuclear receptors that regulate metabolism. Further, increasing plasma bile acids – by feeding mice ursodeoxycholic acid, treating mice with broad-spectrum antibiotics, or raising mice germ-free– is sufficient to protect functional beta cell mass against the beta-cell toxin, streptozotocin. Intriguingly, we also found reduced bile salt hydrolase (BSH) activity in cecum, where most gut microbiota reside, and increased GLP1 in pancreatic alpha-cells. To understand the physiological and molecular mechanisms underlying MGAT2 deficiency-mediated protection, we propose here to rigorously test our overarching hypothesis that that loss of intestinal MGAT2 (1) decreases microbial BSH activity, which (2) enhances reabsorption through the apical sodium-dependent bile salt transporter (ASBT), leading to (3) increased GLP1 secretion from pancreatic a-cells that induces GLP1 receptor (GLP1r)-signaling in b-cells, and thereby protects pancreatic islet function. In Aim 1, we will determine if a reduction in BSH activity is necessary and/or sufficient to increase plasma bile acids and protect mice again beta cell insults. In Aim 2, we will determine if loss of MGAT2 enhances re-absorption of bile acids and if the process requires ASBT. In Aim 3, we will determine if GLP1 produced in alpha cells and if GLP1 receptors on beta cells are required for the effects of MGAT2 deficiency. Our proposed work represents essential steps to elucidate novel pathways that link intestinal lipid processing and bile acid metabolism with pancreatic islet function. Our findings will describe a novel example of interorgan communication that controls systemic metabolism setting the stage for targeting MGAT2 inhibition to combat diabetes by decreasing bacterial bile salt hydrolase, increasing conjugated primary bile acids, and modulating intra-islet signaling.

糖尿病的患病率在美国达到了流行比例，严重困扰着患者，并以生产力损失和医疗保健费用烧毁了社会。糖尿病的特征是胰腺中的β细胞质量减少，或者β细胞无法秘密胰岛素秘密以完全补偿胰岛素耐药性。增加或保存功能性β细胞量是预防或治疗糖尿病的有吸引力的目标；但是，我们的干预目标不足。我们研究的长期目标是更好地了解肠道脂质加工如何控制系统性代谢并探索干预目标以对抗代谢疾病。我们报道说，酰基COA：单酰基甘油烯基转移酶2（MGAT2）介导肠道脂肪的吸收并调节全身能量平衡。尽管缺乏功能性MGAT2基因（mogat2 - / - ）或缺乏MGAT2的小鼠令人着迷，但我们发现MGAT2的损失通过保存功能性β细胞量来保护小鼠免受化学和遗传诱导的糖尿病的侵害。与保护相关的MoGat2 - / - 小鼠具有增加血浆胆汁酸的增加，该血浆胆酸具有潜在的代谢作用，作为调节代谢的膜和核受体的配体。此外，增加血浆胆汁酸的增加 - 通过喂养小鼠ursoxyoxycholic，用宽光谱抗生素治疗小鼠或提高小鼠无菌的小鼠足以保护功能性β细胞质量，以防止β-细胞毒素抗蛋白链球菌链球菌链球菌素。有趣的是，我们还发现了大多数肠道微生物群居住的Cecum的胆汁盐水解酶（BSH）活性降低，并且在胰腺α-细胞中增加了GLP1。为了了解MGAT2缺乏介导的保护的背后的物理和分子机制，我们在这里提议严格测试我们的总体假设，即肠内MGAT2（1）的丧失会增加微生物BSH的活性，（2）通过依赖于依赖的胆汁含量的bile salt tomporter perter（3）增强了（2），从而增强了apical s salt perter（3），从而增加了glpp1（3）。在AIM 2中，我们将确定MGAT2的丢失是否增强了胆汁酸的重新吸收以及该过程是否需要ASBT。在AIM 3中，我们将确定是否需要在α细胞中产生的GLP1以及MGAT2缺乏效果的β细胞上的GLP1受体是否需要。我们提出的工作代表了阐明新型途径的基本步骤，这些途径将肠道脂质加工和胆汁酸代谢与胰岛功能联系起来。我们的发现将描述一个新颖的组织内部通信的新例子，该新例子控制着系统性代谢为靶向MGAT2抑制以通过减少细菌胆汁盐水解酶，增加共轭原代胆汁酸并调节液体内信号来对抗糖尿病的阶段。