Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-κB
Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-κB
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DOI：
10.1074/jbc.m312692200
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发表时间：
2004-06-04
影响因子：
4.8
通讯作者：
Schleicher, ED
中科院分区：
文献类型：
--
作者：
Weigert, C;Brodbeck, K;Schleicher, ED
肥胖和2型糖尿病患者的循环白细胞介素-6（IL-6）、胰岛素和游离脂肪酸（FFA）浓度与胰岛素作用受损相关。然而，血浆游离脂肪酸升高与IL-6之间的因果关系尚未得到证实。由于骨骼肌是胰岛素作用受损的主要靶点，我们研究了游离脂肪酸是否会影响人肌管中IL-6的表达。我们证明，特别饱和的FFA，e。G.棕榈酸酯（0.25 mM）通过蛋白酶体依赖性机制诱导IL-6 mRNA表达和蛋白分泌，该机制导致核因子-κ B的快速和慢性活化。胰岛素、高浓度葡萄糖或不饱和脂肪酸不能激活IL-6的表达。事实上，不饱和FFA亚油酸酯抑制棕榈酸诱导的IL-6产生。由于酰基辅酶A合成酶抑制剂三酸甘油酯C对棕榈酸酯代谢的抑制并没有消除IL-6的表达，因此似乎棕榈酸酯分子本身发挥了所观察到的作用。此外，我们表明，在人类肌管，IL-6激活磷酸化的信号转导和转录激活因子3的浓度类似于肝细胞。然而，没有抑制作用的IL-6对胰岛素的作用，确定为磷脂酰肌醇3-激酶与胰岛素受体底物1，Akt磷酸化，糖原合成，被检测到。我们的结论是，IL-6的表达可能是由循环FFA的组成，如调节。G.骨骼肌细胞可能是IL-6的靶细胞。
Circulating interleukin-6 (IL-6), insulin, and free fatty acid (FFA) concentrations are associated with impaired insulin action in obese and type 2 diabetic individuals. However, a causal relationship between elevated plasma FFAs and IL-6 has not been shown. Because skeletal muscle represents a major target of impaired insulin action, we studied whether FFAs may affect IL-6 expression in human myotubes. We demonstrate that specifically saturated FFAs, e. g. palmitate (0.25 mM), induce IL-6 mRNA expression and protein secretion by a proteasome-dependent mechanism that leads to a rapid and chronic activation of nuclear factor-kappaB. Insulin, high glucose concentrations, or unsaturated FFAs did not activate IL-6 expression. In fact, the unsaturated FFA linoleate inhibited palmitate-induced IL-6 production. Because inhibition of palmitate metabolism by the acyl-CoA synthetase inhibitor triacsin C did not abolish IL-6 expression, it appears that the palmitate molecule per se exerts the observed effects. Furthermore, we show that in human myotubes, IL-6 activates the phosphorylation of signal transducer and activator of transcription 3 in concentrations similar to hepatocytes. However, no inhibitory effect of IL-6 on insulin action, determined as phosphatidylinositol 3-kinase association with insulin receptor substrate-1, Akt phosphorylation, and glycogen synthesis, was detected. We conclude that IL-6 expression may be modulated by the composition of circulating FFA, e. g. by diet, and that skeletal muscle cells could be target cells for IL-6.