THE ENDOTHELIAL PPARy-RXR TRANSCRIPTIONAL COMPLEX IN THE CONTROL OF METABOLISM

内皮 PPARy-RXR 转录复合物在代谢控制中的作用

• 批准号: 7975785
• 负责人: JORGE PLUTZKY
• 金额: $ 40.99万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-21 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7975785
• 关键词: Adipose tissue; Anti-Inflammatory Agents; Anti-inflammatory; Arteries; Atherosclerosis; Biology; Blood Vessels; Bone Marrow Transplantation; Cells; Collaborations; Complex; Data; Diabetes Mellitus; Diet; Dyslipidemias; Endothelial Cells; Endothelium; Enzymes; Equilibrium; Exposure to; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Genes; Glucose; Glycerol; Goals; Heart Diseases; Hematopoietic; Hepatic; Hyperglycemia; Inflammation; Inflammatory; Inflammatory Response; Laboratories; Leukocytes; Ligands; Maintenance; Metabolic; Metabolism; Mus; Nonesterified Fatty Acids; Obesity; Oxidants; Oxidation-Reduction; Oxidative Stress; PPAR gamma; Pathway interactions; Patients; Phenotype; Post-Translational Protein Processing; Proteins; RXR; Receptor Activation; Reporting; Repression; Resources; Retinaldehyde; Retinoids; Retinol Binding Proteins; Role; Source; Staging; Tretinoin; Triglyceride Metabolism; Triglycerides; Vasomotor; Work; Xanthine Dehydrogenase; activating transcription factor; chemokine; energy balance; fatty acid oxidation; feeding; glutathione peroxidase; improved; in vivo; insight; insulin sensitivity; mouse model; novel; oxidant stress; oxidation; receptor; response; retinaldehyde dehydrogenase; uptake

The peroxisome proliferator-activated receptor gamma-retinoid X receptor (PPARy-RXR) transcriptional complex regulates energy balance by controlling genes involved in the metabolism, uptake, oxidative combustion and storage of fatty acids (FAs) and glucose. The PPARy-RXR complex also modulates inflammation, oxidant stress and atherosclerosis, including through their effects in the endothelium. Although endothelial function is usually defined in terms of vasomotor reactivity, we hypothesize the endothelium is also involved in the control of systemic metabolism. We found that endothelial PPARy-deficient mice fed a high fat diet manifest decreased adiposity and improved insulin sensitivity but markedly elevated FA and triglyceride (TG) levels and impaired endothelial reactivity, all as compared to control mice. As such, these mice (Tie2Cre/floxed PPARy mice with and without bone marrow transplantation) disassociate metabolic and vascular components of endothelial function, providing opportunities for studying endothelial control of metabolism. Aim 1 will investigate how endothelial PPARy's control of FA and glycerol levels influences endothelial responses, hepatic TG accumulation and insulin sensitivity. Aim 2 will investigate the source of the increased oxidant stress evident in endothelial PPARydeficient mice, including the role of oxidation in endogenous PPARy ligand formation. Although we and others have shown that PPARy can inhibit endothelial inflammatory responses, including endothelial chemokine expression, the mechanisms for this trans-repression have remained unclear. Aim 3 will investigate the evidence provided here that post-translatioiial SUMOylation of PPARy is involved in PPARymediated repression of specific chemokine subsets and leukocyte recruitment, including inflammatory cell recruitment to adipose tissue. Although all these and other PPARy actions require RXR as an obligate heterodimeric PPARy partner, very little is known about the role of retinoid metabolism and RXR activation in the endothelium. We recently reported that retinaldehyde, which is converted by retinaldehyde dehydrogenase (RaIdh) to retinoic acid (RA), is present in fat where it can repress PPARy-RXR activity. Raldhi-deficient mice, which have increased Raid in fat, are completely protected against diet-induced obesity and diabetes. Aim 4 will investigate pathways of retinoid metabolism in endothelial cells and the sources of the increased oxidant stress in Raldhi-deficient mice shown here. Together these studies, through close collaboration with the other Projects and Core Laboratories, will identify how the endothelial PPARy-RXR complex is involved in integrating metabolic and vascular components of endothelial function.

过氧化物酶体增殖物激活受体 γ-视黄醇 X 受体 (PPARy-RXR) 转录复合物通过控制参与脂肪酸（FA）和葡萄糖的代谢、摄取、氧化燃烧和储存的基因来调节能量平衡。 PPARγ-RXR 复合物还调节炎症、氧化应激和动脉粥样硬化，包括通过其在内皮细胞中的作用。尽管内皮功能通常是根据血管舒缩反应性来定义的，但我们 假设内皮细胞也参与全身代谢的控制。我们发现 与对照小鼠相比，内皮 PPARγ 缺陷小鼠在高脂肪饮食下表现出肥胖减少和胰岛素敏感性改善，但 FA 和甘油三酯 (TG) 水平显着升高，内皮反应性受损。因此，这些小鼠（接受或不接受骨髓移植的 ​​Tie2Cre/floxed PPARy 小鼠）分离内皮功能的代谢和血管成分，为研究代谢的内皮控制提供了机会。目标 1 将研究内皮 PPARγ 对 FA 和甘油水平的控制如何影响内皮反应、肝脏 TG 积累和胰岛素敏感性。目标 2 将研究内皮 PPARγ 缺陷小鼠中明显增加的氧化应激的来源，包括氧化在内源性 PPARγ 配体形成中的作用。尽管我们和其他人已经证明 PPARγ 可以抑制内皮炎症反应，包括内皮趋化因子表达，但这种反式抑制的机制仍不清楚。目标 3 将调查此处提供的证据，即 PPARy 的翻译后 SUMO 化参与 PPARy 介导的特定趋化因子亚群的抑制和白细胞募集，包括炎症细胞募集到脂肪组织。尽管所有这些和其他 PPARγ 作用都需要 RXR 作为专性异二聚体 PPARγ 伴侣，但人们对内皮中类视黄醇代谢和 RXR 激活的作用知之甚少。我们最近报道了视黄醛，它是由视黄醛转化而来 脱氢酶 (RaIdh) 转化为视黄酸 (RA)，存在于脂肪中，可以抑制 PPARy-RXR 活性。 缺乏 Raldhi 的小鼠，其脂肪 Raid 增加，完全可以免受饮食引起的肥胖和糖尿病的影响。目标 4 将研究内皮细胞中类维生素A代谢的途径以及此处显示的 Raldhi 缺陷小鼠中氧化应激增加的来源。通过与其他项目和核心实验室的密切合作，这些研究将共同​​确定内皮 PPARγ-RXR 复合物如何参与整合内皮功能的代谢和血管成分。