Systems genetics approaches to bile acid metabolisms

胆汁酸代谢的系统遗传学方法

基本信息

批准号：
9109009
负责人：
Karen Reue
金额：
$ 58.59万
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：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9109009
关键词：
Affect Apical Arterial Fatty Streak Atherosclerosis Bile Acid Biosynthesis Pathway Bile Acids Biliary Binding Biochemical Blood Circulation Candidate Disease Gene Cell physiology Cholelithiasis Cholesterol Code Complex Development Diabetes Mellitus Diarrhea Disease remission Enterocytes Enterohepatic Circulation Excretory function Fat-Soluble Vitamin Fatty acid glycerol esters Feces Feedback Fibroblast Growth Factor Gallbladder Gastrointestinal tract structure Genes Genetic Genetic Transcription Genetic study Glucose Goals Hepatic Hepatocyte Homeostasis Human Human Genetics Hybrids Hyperlipidemia Hypertriglyceridemia In Vitro Individual Insulin Insulin Resistance Intestinal Absorption Intestines Knowledge Ligands Lipids Liver Liver diseases Maintenance Maps Metabolic Metabolic Diseases Metabolic syndrome Metabolism Mexican Micelles Molecular Molecular Genetics Mouse Strains Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Orthologous Gene Pathway interactions Physiological Plasma Play Production Proteins Rare Diseases Regulation Regulatory Pathway Repression Research Resistance Resolution Resources Role Route Serum Signal Transduction Small Intestines Surface System Transcriptional Regulation Triglycerides Variant Vitamins bariatric surgery blood glucose regulation cell growth regulation cholesterol absorption cohort fascinate feeding genetic approach genetic association genetic resource genetic variant genome-wide gut microbiome gut microbiota ileum in vivo man microbiota mouse model non-alcoholic fatty liver novel novel strategies null mutation protein function receptor response trafficking trait uptake

项目摘要

SUMMARY Project 2 Bile acids have long been known to be critical for efficient intestinal absorption of fats and lipid-soluble vitamins. Recent studies reveal that bile acids have widespread metabolic effects, and are associated with key components of the metabolic syndrome (MetSyn), including glucose/insulin homeostasis, plasma lipid levels, and maintenance of gut microbiota. Bile acid homeostasis is maintained via complex regulatory mechanisms, with many components still being incompletely understood. A fascinating aspect of bile acid homeostasis is the coordination between bile acid uptake in intestine and the control of bile acid synthesis in liver. We recently used a genetic approach to identify the Diet1 gene, and determined that Diet1 acts as a control point for the intestinal production of fibroblast growth factor 15/19 (FGF15/19), which signals in liver to repress bile acid synthesis. Mice with a Diet1 null mutation have reduced FGF15 secretion, causing impaired feedback repression of hepatic bile acid synthesis, and increased fecal bile acid excretion. As a result, these mice are resistant to hyperlipidemia and atherosclerotic lesions. Due to its recent identification, many aspects of Diet1 function are unknown. In Specific Aim 1, we will further characterize the molecular and physiological role of Diet1 in bile acid homeostasis, glucose homeostasis, and effects on gut microbiome composition. We will also evaluate the effects of DIET1 genetic variants on bile acid levels and MetSyn traits. In Specific Aim 2, we will identify novel genetic loci that determine bile acid levels using the hybrid mouse diversity panel (HMDP), an unparalleled resource for genetic association of loci for complex traits. We have mapped loci for biliary, fecal, and plasma bile acid levels at high resolution to loci containing only 6-16 candidate genes. We will identify the causative genes using a combination of genetic, biochemical, molecular, and in vivo approaches. We will evaluate genes identified in the mouse for association with bile acid levels and MetSyn traits in the METSIM cohort, with 3500 individuals typed for bile acid levels. Our studies are made possible by mouse and human genetic resources that are unique to our PPG, and our findings will contribute to the overall goal of identifying genes that contribute to MetSyn traits.

概括项目2 长期以来，胆汁酸对于有效的脂肪和脂溶性肠道吸收至关重要维生素。最近的研究表明，胆汁酸具有广泛的代谢作用，并且与关键有关代谢综合征（METSYN）的成分，包括葡萄糖/胰岛素稳态，血浆脂质水平，和肠道菌群的维护。通过复杂的调节机制来维持胆汁酸稳态，由于许多组件仍未得到完全理解。胆汁酸稳态的一个有趣的方面是胆酸吸收肠与肝脏合成肝脏合成之间的配位。我们最近使用遗传学方法来识别Diet1基因，并确定Diet1充当了成纤维细胞生长因子的肠产生15/19（FGF15/19），该因子在肝脏中发出信号以抑制胆汁酸合成。 Diet1无效突变的小鼠减少了FGF15的分泌，导致反馈受损抗肝胆酸合成的抑制，并增加了粪便胆酸排泄。结果，这些老鼠是对高脂血症和动脉粥样硬化病变具有抗性。由于其最近的识别，Diet1的许多方面功能未知。在特定目标1中，我们将进一步表征胆汁酸稳态，葡萄糖稳态以及对肠道微生物组组成的影响。我们也会评估Diet1遗传变异对胆汁酸水平和Metsyn特征的影响。在特定的目标2中，我们将识别使用混合小鼠多样性面板（HMDP）确定胆汁酸水平的新型遗传基因座，复杂性状的基因座遗传关联的无与伦比的资源。我们已经为胆道绘制了粪便，粪便高分辨率的血浆胆汁酸水平仅包含6-16个候选基因。我们将确定结合遗传，生化，分子和体内方法的结合。我们将评估在小鼠中鉴定的基因与MetSim中的胆汁酸水平和Metsyn性状缔合队列，有3500个为胆汁酸水平的个体。我们的研究是由老鼠和人类成为可能的我们PPG独有的遗传资源，我们的发现将有助于确定的总体目标有助于Metsyn特征的基因。