Retinoic Acid, Its Receptors, and the Liver

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。它们在皮肤、眼睛和多种癌症中的作用已被广泛研究。肝脏是维甲酸（RA）的主要靶点。令人惊讶的是，类风湿性关节炎在肝脏中的作用很少受到关注。我们过去10年的数据揭示了类维生素a在肝脏中的许多新作用。我们发现，在肝脏中，类维甲酸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的稳态。此外，肝类视黄醛信号传导调节细胞增殖和凋亡以及炎症。因此，我们假设RA及其受体在一般情况下调节肝脏代谢和功能。当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（类维生素a x受体1）缺乏增加，RA治疗降低了体内血脂。此外，肝脏RXR1的缺乏增加了脂肪变性和脂肪性肝炎的易感性。提出了三个具体的目的来研究RA/受体在肝脏中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肝脏全基因组RA/受体靶基因/途径。生成的数据可以解释肝功能和对肝脏疾病易感性的性别差异。目的2研究类视黄醇介导途径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，要么对RA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通过修饰染色质结构和表观遗传特征来调节基因的假设。在肝脏中，类视黄醇信号在基础和ra调控水平上受到控制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首次尝试揭示类视黄醇信号在肝脏内的基本作用，重点是脂质稳态。产生的数据将对癌症、代谢综合征、糖尿病、心血管疾病以及毒理学产生巨大影响。

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. PUBLIC HEALTH RELEVANCE: The action of retinoids in the liver has received very little attention. We show that retinoids and their receptors have a broad spectrum of actions ranging from xenobiotic biotransformation to lipid, carbohydrate, and amino acid homeostasis in the liver. The proposed project will profile hepatic genome-wide RA receptor target-gene in a gender specific manner and elucidate the mechanism by which RA and its receptors regulate lipid homeostasis and its own signaling. The generated data will have a significant impact on conditions including but not limited to metabolic syndrome, cancer, toxicology, diabetes, and cardiovascular disease.