Retinoic Acid, Its Receptors, and the Liver

视黄酸、其受体和肝脏

• 批准号: 8465227
• 负责人: Yu-Jui Yvonne Wan
• 金额: $ 32.32万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465227
• 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 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; 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; 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 a 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 serum lipids and RA treatment reduces them 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 difference 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 expressions. The transcriptional machinery, which dictates RA responsiveness, will be elucidated. Aim 3 studies the basal and RA-induced transcriptional machinery mediated by hepatic RXR1. We focus on PDK4, RAR2, and Cyp26a1 because our novel data show that these genes are induced by RA treatment as well as RXR1 deficiency. These genes have functional significance in either lipid homeostasis or RA efficacy. How retinoid signaling is controlled at the basal and RA-regulated level will be determined. 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（由申请人提供）：类维生素A具有广泛的作用，包括发育、生长、细胞死亡和抗氧化。它们的作用已在皮肤、眼睛和多种癌症中得到广泛研究。肝脏是视黄酸 (RA) 的主要靶点。令人惊讶的是，RA 在肝脏中的作用很少受到关注。我们在过去 10 年中生成的数据揭示了类视黄醇在肝脏中的许多新作用。我们发现，在肝脏中，类视黄醇及其受体具有广泛的作用，从外源生物转化到胆固醇、脂肪酸、胆汁酸、碳水化合物和氨基酸稳态。此外，肝脏类维生素A信号传导调节细胞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代谢和功能。当前应用的目标是双重的：以性别特异性的方式提供肝脏全基因组RA受体靶基因谱，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/受体在调节脂质稳态中的作用，因为肝细胞 RXR1（类视黄醇 x 受体 1）缺乏会增加血清脂质，而 RA 治疗会降低体内血清脂质。此外，肝脏 RXR1 的缺乏会增加发生脂肪变性和脂肪性肝炎的易感性。提出了三个具体目标来研究 RA/受体在肝脏中的整体效应及其潜在机制。目标 1 使用 ChIP 测序和微阵列分析以性别特异性方式确定肝脏中全基因组 RA/受体靶基因/通路。生成的数据可以解释肝功能和肝病易感性的性别差异。目标 2 研究类维生素A介导的途径调节脂质稳态的机制。我们建议研究调节两个脂质稳态基因簇的机制，这两个基因对 RA 要么有反应，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。目标 3 研究肝脏 RXR1 介导的基础转录机制和 RA 诱导的转录机制。我们重点关注 PDK4、RAR2 和 Cyp26a1，因为我们的新数据表明这些基因是由 RA 治疗以及 RXR1 缺陷诱导的。这些基因在脂质稳态或 RA 功效中具有功能意义。如何在基础和 RA 调节水平上控制类维生素A信号传导将被确定。拟议的研究可能是首次尝试揭示类维生素A信号在肝脏内的基本影响，重点是脂质稳态。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。