Palmitate induces tumor necrosis factor-α expression in C2C12 skeletal muscle cells by a mechanism involving protein kinase C and nuclear factor-κB activation
Palmitate induces tumor necrosis factor-α expression in C2C12 skeletal muscle cells by a mechanism involving protein kinase C and nuclear factor-κB activation
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DOI：
10.1210/en.2005-0440
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发表时间：
2006-01-01
期刊：
影响因子：
4.8
通讯作者：
Vázquez-Carrera, M
中科院分区：
文献类型：
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作者：
Jové, M;Planavila, A;Vázquez-Carrera, M
糖尿病状态下骨骼肌细胞中 TNF-α 表达增加的机制尚不清楚。我们研究了饱和酸棕榈酸酯对 TNF-α 表达的影响。将 C2C12 骨骼肌细胞暴露于 0.75 mM 棕榈酸酯可增强促炎细胞因子 TNF-α 的 mRNA（诱导 25 倍，P < 0.001）和蛋白质（诱导 2.5 倍）表达。这种诱导与 GLUT4 mRNA 水平（减少 57%，P < 0.001）和葡萄糖摄取（减少 34%，P < 0.001）的下降呈负相关。 PD98059 和 U0126 是 ERK-MAPK 级联的抑制剂，部分阻止棕榈酸酯诱导的 TNF-α 表达。棕榈酸增加了核因子 (NF)-κ B 的激活，并且细胞与 NF-κ B 抑制剂吡咯烷二硫代氨基甲酸酯和小白菊内酯一起孵育可部分阻止 TNF-α 的表达。将棕榈酸酯处理的细胞与钙磷蛋白 C（一种强效且特异性的蛋白激酶 C (PKC) 抑制剂）一起孵育，可消除棕榈酸酯诱导的 TNF-α 表达，并恢复 GLUT4 mRNA 水平。棕榈酸酯处理增强了磷酸化 PKC theta 的表达，表明这种 PKC 亚型参与了所报告的变化，并且棕榈酸酯处理的细胞与 PKC 抑制剂白屈菜红碱共孵育可防止棕榈酸酯诱导的 I kappa B α 表达减少和胰岛素刺激的 Akt 激活。这些发现表明，棕榈酸酯引起的 TNF-α 表达增强和 GLUT4 下调是通过 PKC 激活介导的，证实该酶可能是预防或治疗脂肪酸诱导的胰岛素抵抗的靶标。
The mechanisms responsible for increased expression of TNF-alpha in skeletal muscle cells in diabetic states are not well understood. We examined the effects of the saturated acid palmitate on TNF-alpha expression. Exposure of C2C12 skeletal muscle cells to 0.75 mM palmitate enhanced mRNA (25-fold induction, P < 0.001) and protein (2.5-fold induction) expression of the proinflammatory cytokine TNF-alpha. This induction was inversely correlated with a fall in GLUT4 mRNA levels (57% reduction, P < 0.001) and glucose uptake (34% reduction, P < 0.001). PD98059 and U0126, inhibitors of the ERK-MAPK cascade, partially prevented the palmitate-induced TNF-alpha expression. Palmitate increased nuclear factor (NF)-kappa B activation and incubation of the cells with the NF-kappa B inhibitors pyrrolidine dithiocarbamate and parthenolide partially prevented TNF-alpha expression. Incubation of palmitate-treated cells with calphostin C, a strong and specific inhibitor of protein kinase C (PKC), abolished palmitate-induced TNF-alpha expression, and restored GLUT4 mRNA levels. Palmitate treatment enhanced the expression of phospho-PKC theta, suggesting that this PKC isoform was involved in the changes reported, and coincubation of palmitate-treated cells with the PKC inhibitor chelerythrine prevented the palmitate-induced reduction in the expression of I kappa B alpha and insulin-stimulated Akt activation. These findings suggest that enhanced TNF-alpha expression and GLUT4 down-regulation caused by palmitate are mediated through the PKC activation, confirming that this enzyme may be a target for either the prevention or the treatment of fatty acid-induced insulin resistance.