The peroxisome proliferator-activated receptor β/δ agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells
The peroxisome proliferator-activated receptor β/δ agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells
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DOI：
10.1210/me.2003-0151
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发表时间：
2003-12-01
影响因子：
--
通讯作者：
Muscat, GEO
中科院分区：
文献类型：
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作者：
Dressel, U;Allen, TL;Muscat, GEO
脂质体内平衡由过氧化物酶体增殖物激活受体（PPARalpha、-β/δ和-γ）控制，其作为调节脂质代谢的脂肪酸依赖性DNA结合蛋白发挥作用。体外和体内遗传学和药理学研究表明，PPARalpha调节脂质过氧化反应。相反，PPARgamma调节脂质储存的冲突过程。然而，对PPARbeta/delta在靶组织、靶基因、脂质体内平衡以及与PPARalpha和-gamma的功能重叠的背景下知之甚少。PPARbeta/delta是一种极低密度脂蛋白传感器，在骨骼肌中大量表达，骨骼肌是占总体重约40%的主要外周组织。骨骼肌是代谢活性组织，并且是葡萄糖代谢、脂肪酸氧化和胆固醇流出的主要部位。因此，它在胰岛素敏感性、血脂谱和脂质稳态中具有重要作用。令人惊讶的是，PPARbeta/delta在骨骼肌中的作用尚未研究。我们利用选择性PPARalpha，-β/δ，-γ，和肝X受体激动剂在骨骼肌细胞中，以了解PPARbeta/δ的功能作用，和PPARs在这个主要的质量外周组织的互补和/或对比作用。通过GW 501516激活骨骼肌细胞中的PPARbeta/delta，诱导参与优先脂质利用、β-氧化、胆固醇流出和能量解偶联的基因的表达。此外，我们表明，用GW 501516处理肌细胞增加了细胞内胆固醇的载脂蛋白-A1特异性流出，从而将该组织鉴定为PPARbeta/delta激动剂的重要靶点。有趣的是，非诺贝特诱导参与果糖摄取和糖原形成的基因。相反，罗格列酮介导的PPARgamma激活诱导与葡萄糖摄取、脂肪酸合成和脂质储存相关的基因表达。此外，我们表明，肌肉肉毒碱棕榈酰转移酶-1启动子中的PPAR-dependent报告直接受PPARbeta/delta调节，而不是PPARalpha在骨骼肌细胞中以PPARgamma共激活因子-1依赖的方式。这项研究表明，PPARs在骨骼肌细胞中具有独特的作用，调节脂质，碳水化合物和能量稳态。此外，我们推测PPARgamma/delta激动剂会增加脂肪酸催化剂，胆固醇流出和肌肉能量消耗，并推测PPARbeta/delta的选择性激活剂可能在治疗高脂血症，动脉粥样硬化和肥胖症中具有治疗效用。
Lipid homeostasis is controlled by the peroxisome proliferator-activated receptors (PPARalpha, -beta/delta, and -gamma) that function as fatty acid-dependent DNA-binding proteins that regulate lipid metabolism. In vitro and in vivo genetic and pharmacological studies have demonstrated PPARalpha regulates lipid catabolism. In contrast, PPARgamma regulates the conflicting process of lipid storage. However, relatively little is known about PPARbeta/delta in the context of target tissues, target genes, lipid homeostasis, and functional overlap with PPARalpha and -gamma. PPARbeta/delta, a very low-density lipoprotein sensor, is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for approximately 40% of total body weight. Skeletal muscle is a metabolically active tissue, and a primary site of glucose metabolism, fatty acid oxidation, and cholesterol efflux. Consequently, it has a significant role in insulin sensitivity, the blood-lipid profile, and lipid homeostasis. Surprisingly, the role of PPARbeta/delta in skeletal muscle has not been investigated. We utilize selective PPARalpha, -beta/delta, -gamma, and liver X receptor agonists in skeletal muscle cells to understand the functional role of PPARbeta/delta, and the complementary and/or contrasting roles of PPARs in this major mass peripheral tissue. Activation of PPARbeta/delta by GW501516 in skeletal muscle cells induces the expression of genes involved in preferential lipid utilization, beta-oxidation, cholesterol efflux, and energy uncoupling. Furthermore, we show that treatment of muscle cells with GW501516 increases apolipoprotein-A1 specific efflux of intracellular cholesterol, thus identifying this tissue as an important target of PPARbeta/delta agonists. Interestingly, fenofibrate induces genes involved in fructose uptake, and glycogen formation. In contrast, rosiglitazone-mediated activation of PPARgamma induces gene expression associated with glucose uptake, fatty acid synthesis, and lipid storage. Furthermore, we show that the PPAR-dependent reporter in the muscle carnitine palmitoyltransferase-1 promoter is directly regulated by PPARbeta/delta, and not PPARalpha in skeletal muscle cells in a PPARgamma coactivator-1-dependent manner. This study demonstrates that PPARs have distinct roles in skeletal muscle cells with respect to the regulation of lipid, carbohydrate, and energy homeostasis. Moreover, we surmise that PPARgamma/delta agonists would increase fatty acid catabolism, cholesterol efflux, and energy expenditure in muscle, and speculate selective activators of PPARbeta/delta may have therapeutic utility in the treatment of hyperlipidemia, atherosclerosis, and obesity.