Retinoic Acid, Its Receptors, and the Liver

视黄酸、其受体和肝脏

• 批准号: 8296548
• 负责人: Yu-Jui Yvonne Wan
• 金额: $ 6.6万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-06 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296548
• 关键词: ADD-1 protein; Accounting; Address; Alcohols; All-Trans-Retinol; Amino Acids; Apoptosis; Attention; Bile Acids; Carbohydrates; Cardiovascular Diseases; Cell Death; Cell Proliferation; ChIP-seq; Cholesterol; Chromatin Structure; Data; Diabetes Mellitus; Disease; Epigenetic Process; Eye; Fatty Acids; Gender; Gene Cluster; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Growth and Development function; Hepatic; Hepatocyte; Homeostasis; Inflammation; Lipids; Liver; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metabolic Biotransformation; Metabolic syndrome; Metabolism; Microarray Analysis; Modification; Molecular; Mus; Nuclear Receptors; Organ; Pathway interactions; Pattern; Play; Predisposition; Prevention strategy; Process; RXR; Regulation; Retinoic Acid Receptor; Retinoids; Role; Serum; Sex Characteristics; Signal Transduction; Site; Skin; Solid; Stearoyl-CoA Desaturase; Steatohepatitis; Testing; Toxic effect; Toxicology; Tretinoin; Triglycerides; Xenobiotics; cancer type; design; fatty acid elongases; feeding; genome wide association study; genome-wide; in vivo; lipid metabolism; liver function; liver metabolism; novel; oxidation; pyruvate dehydrogenase kinase 4; receptor; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Retinoids have broad effects including development, growth, cell death, and anti-oxidation. Their actions have been extensively studied in the skin, eye, and in many types of cancer. The liver is a major retinoic acid (RA) target site. Surprisingly, the action of RA in the liver has received very little attention. Our data generated in the past 10 years have uncovered many novel roles of retinoids in the liver. We showed that in the liver retinoids and their receptors have a broad spectrum of actions ranging from xenobiotic biotransformation to cholesterol, fatty acid, bile acid, carbohydrate, and amino acid homeostasis. In addition, hepatic retinoid signaling regulates cell proliferation and apoptosis as well as inflammation. Thus, we hypothesize that RA and its receptors regulate liver metabolism and function in general. The objective for the current application is twofold: to provide an unbiased hepatic genome-wide RA receptor target-gene profile in a gender-specific manner and to elucidate the mechanism by which RA and its receptors regulate gene transcription and expression. Among the diverse pathways, we propose to focus on studying the role of RA/receptors in regulating lipid homeostasis because hepatocyte RXR1 (retinoid x receptor 1) deficiency increases and RA treatment reduces serum lipids in vivo. Furthermore, lack of hepatic RXR1 increases the susceptibility to develop steatosis and steatohepatitis. Three specific aims are proposed to study the global effect of RA/receptors in the liver and the underlying mechanisms. Aim 1 determines genome-wide RA/receptor target genes/pathways in the liver in a gender- specific manner using ChIP-sequencing and microarray analysis. The generated data may account for gender differences in liver function and susceptibility to liver disease. Aim 2 studies the mechanism by which retinoid- mediated pathways regulate lipid homeostasis. We propose to study the mechanisms that regulate two clusters of lipid homeostasis genes, which either do or do not respond to RA but both depend on hepatic RXR1 for their expression. The transcriptional machinery, which dictates RA responsiveness, will be elucidated. Aim 3 studies the mechanism by which RA regulates its own signaling. We will test the hypothesis that RA and hepatic RXR1 regulate genes via modification of chromatin structure and epigenetic signatures. The mechanism by which retinoid signaling is controlled at the basal and RA-regulated level in the liver will be addressed at the transcriptional and epigenetic level. The proposed study may be the first attempt to uncover the fundamental effects of retinoid signaling within the liver with an emphasis on lipid homeostasis. The generated data will have a huge impact on cancer, metabolic syndrome, diabetes, and cardiovascular disease as well as toxicology.

描述(申请人提供)：维甲酸具有广泛的作用，包括发育、生长、细胞死亡和抗氧化。它们的作用已经在皮肤、眼睛和许多类型的癌症中得到了广泛的研究。肝脏是维甲酸(RA)的主要靶点。令人惊讶的是，RA在肝脏中的作用几乎没有受到关注。我们在过去10年中产生的数据揭示了维甲酸在肝脏中的许多新角色。我们发现，在肝脏中，维甲酸及其受体具有广泛的作用范围，从外来生物转化到胆固醇、脂肪酸、胆汁酸、碳水化合物和氨基酸的动态平衡。此外，肝脏维甲酸信号调节细胞的增殖和凋亡以及炎症。因此，我们假设RA及其受体总体上调节肝脏的代谢和功能。目前应用的目的有两个：以性别特异性的方式提供无偏见的肝脏全基因组RA受体靶基因图谱，并阐明RA及其受体调节基因转录和表达的机制。在多种途径中，我们建议重点研究RA/受体在调节脂质平衡中的作用，因为肝细胞RXR1(视黄酸X受体1)缺陷增加，而RA治疗在体内降低血脂。此外，缺乏肝脏RXR1增加了发生脂肪变性和脂肪性肝炎的易感性。提出了三个特定的目标来研究肝脏中RA/受体的整体作用及其潜在机制。目的1利用芯片测序和微阵列分析，以性别特异性的方式确定全基因组范围的RA/受体在肝脏中的靶基因/通路。生成的数据可能解释了肝功能和肝病易感性的性别差异。目的2研究维甲酸介导的信号转导通路调节脂质稳态的机制。我们建议研究调节两组脂质稳态基因的机制，这两组基因要么对RA有反应，要么没有反应，但都依赖于肝脏RXR1的表达。决定RA反应性的转录机制将被阐明。目的3研究RA调节自身信号转导的机制。我们将验证RA和肝脏RXR1通过修改染色质结构和表观遗传特征来调控基因的假设。维甲酸信号在肝脏中被控制在基础水平和RA调节水平的机制将在转录和表观遗传水平上得到解决。这项拟议的研究可能是第一次试图揭示肝脏内维甲酸信号的基本影响，重点是脂类平衡。生成的数据将对癌症、代谢综合征、糖尿病、心血管疾病以及毒理学产生巨大影响。