Mechanisms of Regulation of Retinoic Acid Homeostasis

视黄酸稳态的调节机制

• 批准号: 9975196
• 负责人: Nina Isoherranen
• 金额: $ 35.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975196
• 关键词: Adipocytes; Adipose tissue; Adult; All-Trans-Retinol; American; Animal Model; Biochemical; Biology; Cardiovascular Diseases; Cells; Clinical Research; Complement; Data; Development; Diabetes Mellitus; Energy Metabolism; Enzymes; Esters; Foundations; Glucose Intolerance; Goals; Health; Health Care Costs; Hepatocyte; Homeostasis; Human; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Insulin Resistance; Interleukin-1; Interleukin-6; Knowledge; Kupffer Cells; Lead; Link; Liver; Malignant neoplasm of liver; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolic syndrome; Metabolism; Methods; Micronutrients; Modeling; Non obese; Obesity; Obesity Epidemic; Population; Process; Public Health; Regulation; Retinoids; Retinol Binding Proteins; Rodent; Rodent Model; Serum; Signal Transduction; Slice; Smoking; System; TNF gene; Testing; Thinness; Time; Tissues; Tretinoin; Visceral; Vitamin A; Vitamin A Deficiency; adipocyte differentiation; cell type; comorbidity; cytokine; enzyme activity; experimental study; glucose metabolism; innovation; insight; kinetic model; lipid metabolism; macrophage; metabolome; non-alcoholic fatty liver disease; novel; novel strategies; obesity development; obesity treatment; pre-clinical; premature; prevent; preventable death; simulation; stellate cell; subcutaneous; targeted treatment; therapy design; therapy development

Obesity is a major public health problem with 38% of American adults being obese and rates of obesity increasing dramatically worldwide. It is estimated that obesity is second only to smoking as a cause of premature preventable death. This is largely due to the comorbidities associated with obesity including metabolic syndrome, diabetes, cardiovascular disease and nonalcoholic fatty liver disease. Yet, very little progress has been made in the development of treatments to prevent obesity and its comorbidities, and the mechanistic link between obesity and development of comorbidities is not completely understood. Several studies have shown that obese rodents develop tissue vitamin A deficiency, with tissue retinoid concentrations decreasing by a stunning 75-90%, suggesting profound metabolic dysregulation. Findings in cell systems and animal models demonstrate that retinoids regulate adipocyte differentiation and glucose and lipid metabolism and, further, that decreased retinoid concentrations are associated with progressive obesity, insulin resistance and glucose intolerance. Thus, aggregate preclinical data suggest that altered vitamin A metabolism may contribute directly to obesity progression and the development of obesity-related co-morbidities. Critically, the mechanisms underlying this dysregulated vitamin A metabolism remain poorly understood, and the relevance of these preclinical findings to human obesity is unclear. A central premise of this proposal is that altered vitamin A metabolism in obesity is a result of increased inflammatory cytokines (IL-1, IL-6 and TNF in metabolic tissues, which regulate the expression of the retinoid metabolizing enzymes CYP26, LRAT, ALDH1A and RDH in adipocytes and various liver cell types. We further hypothesize that this dysregulation of vitamin A metabolism occurs in human obesity as well as in animal models. We will test our hypotheses in two specific aims: 1) to identify the enzymes and the key regulatory signals that control all-trans-retinoic acid (atRA) concentrations and vitamin A metabolic flux in human liver and adipose tissue, and 2) to establish whether adipose tissue and liver vitamin A metabolomes are altered in obese humans. We will use our state-of-the-art mass spectrometry methods, innovative metabolic flux experiments and kinetic modeling in specific cell types to characterize the key enzymes that metabolize retinoids in liver and adipose tissue and determine how the activity of these enzymes is altered in obesity. To determine whether tissue retinoids are altered in human obesity, we will conduct a cross sectional clinical study comparing visceral and subcutaneous adipose tissue, liver and serum vitamin A metabolomes in obese and non-obese subjects. The proposed studies will lay the foundation for understanding the regulation of vitamin A metabolism in human liver and adipose tissue and for determing how vitamin A metabolism may become dysregulated in obesity contributing to progressive obesity and its co-morbidities in humans. The results will generate unprecedented insight into human retinoid biology and ultimately could lead to targeted therapeutic interventions designed to restore tissue retinoid signaling as a novel strategy for the treatment of obesity and its sequela.

肥胖是一个主要的公共健康问题，38%的美国成年人肥胖，肥胖率不断上升 戏剧性地席卷全球。据估计，肥胖是仅次于吸烟的早产原因。 可预防的死亡这主要是由于与肥胖相关的合并症，包括代谢综合征， 糖尿病、心血管疾病和非酒精性脂肪肝。然而，在以下方面进展甚微： 预防肥胖及其合并症的治疗方法的发展，以及肥胖与肥胖之间的机制联系， 和合并症的发展还不完全清楚。几项研究表明，肥胖的啮齿动物 出现组织维生素A缺乏症，组织类维生素A浓度下降惊人的75- 90%， 说明代谢严重失调在细胞系统和动物模型中的发现表明， 类维生素A调节脂肪细胞分化以及葡萄糖和脂质代谢，此外， 这些浓度与进行性肥胖、胰岛素抵抗和葡萄糖耐受不良有关。因此，在本发明中， 综合临床前数据表明，维生素A代谢的改变可能直接导致肥胖 肥胖相关合并症的进展和发展。关键的是，这背后的机制 维生素A代谢失调仍然知之甚少，这些临床前发现与 人类肥胖还不清楚。这一建议的一个中心前提是，肥胖症中维生素A代谢的改变是一个重要的因素。 这是由于代谢组织中炎性细胞因子（IL-1 β、IL-6和TNF α）增加所致，这些细胞因子可调节 类维生素A代谢酶CYP 26、LRAT、ALDH 1A和RDH在脂肪细胞和各种 肝细胞类型我们进一步假设这种维生素A代谢的失调发生在人类肥胖症中 以及在动物模型中。我们将在两个具体目标中检验我们的假设：1）鉴定酶和 控制全反式维甲酸（atRA）浓度和维生素A代谢通量的关键调节信号， 人肝脏和脂肪组织，以及2）确定脂肪组织和肝脏维生素A代谢组是否 在肥胖人群中发生了改变。我们将使用最先进的质谱分析方法， 在特定细胞类型中进行实验和动力学建模，以表征代谢类维生素A的关键酶 在肝脏和脂肪组织中，并确定这些酶的活性如何在肥胖症中改变。以确定 无论组织类维生素A是否在人类肥胖中改变，我们将进行一项横断面临床研究， 肥胖者和非肥胖者的内脏和皮下脂肪组织、肝脏和血清维生素A代谢组 科目这些研究将为了解维生素A代谢的调控奠定基础 在人类肝脏和脂肪组织中，并用于确定维生素A代谢如何在 导致人类进行性肥胖及其共病的肥胖。结果将产生 对人类类维生素A生物学的前所未有的洞察，最终可能导致有针对性的治疗干预 旨在恢复组织类维生素A信号传导，作为治疗肥胖及其后遗症的新策略。