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: 8250447
• 负责人: JORGE PLUTZKY
• 金额: $ 41.06万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250447
• 关键词: Adipose tissue; Anti-Inflammatory Agents; Anti-inflammatory; Arteries; Atherosclerosis; Biology; Blood Vessels; Bone Marrow Transplantation; Cells; Clinical; 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-维甲酸X受体（PPARy-RXR） 转录复合体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。PPARy-RXR复合物还调节炎症、氧化应激和动脉粥样硬化，包括通过它们在内皮中的作用。虽然内皮功能通常是根据血管反应性来定义的，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，喂食高脂肪饮食的内皮PPARy缺陷小鼠表现出肥胖减少和胰岛素敏感性改善，但FA和甘油三酯（TG）水平显著升高，内皮反应性受损。因此，这些小鼠（有和没有骨髓移植的Tie 2Cre/floxed PPARy小鼠）使内皮功能的代谢和血管组分分离，为研究代谢的内皮控制提供了机会。目的1将研究内皮PPARy对FA和甘油水平的控制如何影响内皮反应、肝TG积累和胰岛素敏感性。目的2将研究在内皮细胞PPARy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PPARy配体形成中的作用。虽然我们和其他人已经表明，PPARy可以抑制内皮炎症反应，包括内皮趋化因子的表达，这种反式抑制的机制仍然不清楚。目的3将研究这里提供的证据，即PPARy的垂体后SUMO化参与PPARy介导的特异性趋化因子亚群的抑制和白细胞募集，包括炎性细胞向脂肪组织的募集。尽管所有这些和其他PPARy作用需要RXR作为专性异源二聚体PPARy配偶体，但对类维生素A代谢和RXR活化在内皮中的作用知之甚少。我们最近报道了由视黄醇转化的视黄醇， 在脂肪中存在将PPAR γ-RXR脱氢酶（RaIdh）转化为视黄酸（RA）的酶，在脂肪中它可以抑制PPAR γ-RXR活性。 Raldhi缺陷小鼠，脂肪中的Raid增加，完全防止饮食诱导的肥胖和糖尿病。目的4将研究内皮细胞中类维生素A代谢的途径和在Raldhi缺陷小鼠中增加的氧化应激的来源。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PPARy-RXR复合物如何参与整合内皮功能的代谢和血管成分。