Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes
Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes
复制标题
DOI：
10.1074/jbc.m110.128520
复制
发表时间：
2010-11-05
影响因子：
4.8
通讯作者：
Kanzaki, Makoto
中科院分区：
文献类型：
--
作者：
Tsuchiya, Yo;Hatakeyama, Hiroyasu;Kanzaki, Makoto
升高的饱和FFA（包括棕榈酸盐（C16：0））是外周胰岛素抵抗的主要触发因素，其特征在于骨骼肌中葡萄糖摄取/处置受损，这是由响应胰岛素的GLUT 4易位受损引起的。我们在此证明，棕榈酸诱导下调分拣蛋白，一种分选受体参与胰岛素反应性GLUT 4囊泡的形成，通过涉及PKC θ和TNF-α转化酶的机制，但不是p38，JNK，或线粒体活性氧的产生，导致受损的GLUT 4在C2 C12肌管中的运输。有趣的是，不饱和FFA如棕榈油酸酯（C16：1）和油酸酯（C18：1）没有这种有害作用，而是通过防止异常的PKC θ激活，有效地逆转棕榈酸酯诱导的胰岛素响应性GLUT 4再循环的损伤沿着分拣蛋白丰度的恢复。另一方面，shRNA介导的完整C2 C12肌管中分拣蛋白的减少抑制胰岛素诱导的GLUT 4再循环，而不抑制Akt磷酸化。我们发现，过氧化物酶体增殖物激活受体γ激动剂曲格列酮防止棕榈酸诱导的分拣蛋白减少，也改善了胰岛素反应性GLUT 4再循环，而不改变棕榈酸诱导的信号级联损伤;既不影响高度磷酸化的PKC θ状态，也不影响受损的胰岛素反应性Akt磷酸化。总之，我们的数据提供了新的见解PKC θ依赖性胰岛素抵抗的发病机制与胰岛素反应性GLUT 4易位，这可能不仅通过胰岛素信号转导的缺陷，但也通过减少分拣蛋白，直接控制骨骼肌细胞中的GLUT 4的运输/分选。此外，我们的数据表明，过氧化物酶体增殖物激活受体γ激动剂的胰岛素增敏作用至少部分通过恢复由分拣蛋白控制的适当GLUT 4运输/分选事件来介导。
Elevated saturated FFAs including palmitate (C16:0) are a primary trigger for peripheral insulin resistance characterized by impaired glucose uptake/disposal in skeletal muscle, resulting from impaired GLUT4 translocation in response to insulin. We herein demonstrate that palmitate induces down-regulation of sortilin, a sorting receptor implicated in the formation of insulin-responsive GLUT4 vesicles, via mechanisms involving PKC theta and TNF-alpha-converting enzyme, but not p38, JNK, or mitochondrial reactive oxygen species generation, leading to impaired GLUT4 trafficking in C2C12 myotubes. Intriguingly, unsaturated FFAs such as palmitoleate (C16:1) and oleate (C18:1) had no such detrimental effects, appearing instead to effectively reverse palmitate-induced impairment of insulin-responsive GLUT4 recycling along with restoration of sortilin abundance by preventing aberrant PKC theta activation. On the other hand, shRNA-mediated reduction of sortilin in intact C2C12 myotubes inhibited insulin-induced GLUT4 recycling without dampening Akt phosphorylation. We found that the peroxisome proliferator-activated receptor gamma agonist troglitazone prevented the palmitate-induced sortilin reduction and also ameliorated insulin-responsive GLUT4 recycling without altering the palmitate-evoked insults on signaling cascades; neither highly phosphorylated PKC theta states nor impaired insulin-responsive Akt phosphorylation was affected. Taken together, our data provide novel insights into the pathogenesis of PKC theta-dependent insulin resistance with respect to insulin-responsive GLUT4 translocation, which could occur not only through defects of insulin signaling but also via a reduction of sortilin, which directly controls trafficking/sorting of GLUT4 in skeletal muscle cells. In addition, our data suggest the insulin-sensitizing action of peroxisome proliferator-activated receptor gamma agonists to be at least partially mediated through the restoration of proper GLUT4 trafficking/sorting events governed by sortilin.