Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil.
Department of Biochemistry and Immunology, Ribeirão Preto Medical School - USP, Ribeirão Preto, SP, Brazil.
J Physiol. 2019 Aug;597(16):4277-4291. doi: 10.1113/JP278006. Epub 2019 Jul 17.
We report that the peroxisome proliferator-activated receptor (PPAR)γ coactivator 1-α (PGC-1α)/PPARβ axis is a crucial mediator of uncoupling protein 3 (UCP3) expression in skeletal muscle cells via the transactivativation of a distal PPAR response element at the Ucp3 gene promoter. This mechanism is activated during the myogenic process and by high concentrations of fatty acids independent of PGC-1α protein levels. Ucp3 is essential for PGC-1α-induced oxidative capacity and the adaptive mitochondrial response to fatty acid exposure. These findings provide further evidence for the broad spectrum of the coactivator action in mitochondrial homeostasis, positioning the PGC-1ɑ/PPARβ axis as an essential component of the molecular regulation of Ucp3 gene in skeletal muscle cells.
Uncoupling protein 3 (UCP3) has an essential role in fatty acid metabolism and mitochondrial redox regulation in skeletal muscle. However, the molecular mechanisms involved in the expression of Ucp3 are poorly known. In the present study, we show that the peroxisome proliferator-activated receptor (PPAR)γ coactivator 1-α (PGC-1α)/PPARβ axis is a crucial mediator of Ucp3 expression in skeletal muscle cells. In silico analysis of the UCP3 promoter and quantitative chromatin immunoprecipitation experiments revealed that the induction of the UCP3 transcript is mediated by the transactivation of a distal PPAR response element at the Ucp3 gene promoter by the coactivator PGC-1α. This mechanism is activated during myogenesis and during metabolic stress induced by fatty acids independent of PGC-1α protein levels. We also provide evidence that Ucp3 is essential for PGC-1α-induced oxidative capacity. Taken together, our results highlight PGC-1ɑ/PPARβ as an essential component of the molecular regulation of Ucp3 gene in skeletal muscle cells.
我们报告过，过氧化物酶体增殖物激活受体（PPAR）γ共激活因子 1-α（PGC-1α）/PPARβ 轴是骨骼肌细胞解偶联蛋白 3（UCP3）表达的关键介质，通过 Ucp3 基因启动子上的远端 PPAR 反应元件的反式激活来实现。该机制在成肌过程中以及脂肪酸浓度较高时被激活，而与 PGC-1α 蛋白水平无关。Ucp3 对于 PGC-1α 诱导的氧化能力和对脂肪酸暴露的适应性线粒体反应是必需的。这些发现为共激活因子在维持线粒体平衡方面的广谱作用提供了进一步的证据，将 PGC-1ɑ/PPARβ 轴定位为骨骼肌细胞中 Ucp3 基因分子调控的重要组成部分。
解偶联蛋白 3（UCP3）在脂肪酸代谢和骨骼肌中的线粒体氧化还原调节中具有重要作用。然而，Ucp3 表达的分子机制知之甚少。在本研究中，我们发现过氧化物酶体增殖物激活受体（PPAR）γ共激活因子 1-α（PGC-1α）/PPARβ 轴是骨骼肌细胞中 Ucp3 表达的关键介质。UCP3 启动子的计算机分析和定量染色质免疫沉淀实验表明，UCP3 转录物的诱导是通过共激活因子 PGC-1α 反式激活 Ucp3 基因启动子上的远端 PPAR 反应元件来介导的。该机制在成肌过程中和脂肪酸诱导的代谢应激过程中被激活，而与 PGC-1α 蛋白水平无关。我们还提供了证据表明 Ucp3 对于 PGC-1α 诱导的氧化能力是必需的。综上所述，我们的结果强调了 PGC-1ɑ/PPARβ 轴作为骨骼肌细胞中 Ucp3 基因分子调控的重要组成部分。
