Different impacts of saturated and unsaturated free fatty acids on COX-2 expression in C2C12 myotubes
Different impacts of saturated and unsaturated free fatty acids on COX-2 expression in C2C12 myotubes
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DOI：
10.1152/ajpendo.00293.2009
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发表时间：
2009-12-01
影响因子：
5.1
通讯作者：
Kanzaki, Makoto
中科院分区：
文献类型：
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作者：
Kadotani, Akito;Tsuchiya, Yo;Kanzaki, Makoto
Kadotani A，Tsuchiya Y，Hatakeyama H，Katagiri H，Kanzaki M。饱和和不饱和游离脂肪酸对 C2C12 肌管中 COX-2 表达的不同影响。 Am J Physiol Endocrinol Metab 297：E1291-E1303，2009。首次发表于 2009 年 9 月 15 日； doi:10.1152/ajpendo.00293.2009.-在骨骼肌中，饱和游离脂肪酸 (FFA) 充当促炎刺激物，环氧合酶-2 (COX-2) 是一种在炎症部位诱导的促/抗炎酶，有助于前列腺素的产生。然而，关于骨骼肌中 COX-2 表达的调节及其对 FFA 的反应知之甚少。在此，我们检查了饱和和不饱和 FFA，包括最近鉴定的脂因子（源自脂肪细胞的脂质激素）棕榈油酸酯，作为骨骼肌模型对 C2C12 肌管中 COX-2 表达的影响。将肌管暴露于饱和 FFA [棕榈酸酯 (16:0) 和硬脂酸酯 (18:0)]，但不暴露于不饱和 FFA [棕榈油酸酯 (16:1)、油酸酯 (18:1) 和亚油酸酯 (18:2)]，导致 COX-2 表达缓慢诱导，随后通过涉及 p38 MAPK 和 p38 MAPK 的机制产生前列腺素 E-2。 NF-kappa B 但不是 PKC theta 信号级联。线粒体氧化功能的药理学调节未能干扰 COX-2 表达，表明线粒体超载/过度 β-氧化对此事件的贡献很小。相反，不饱和 FFA 似乎能有效拮抗棕榈酸诱导的 COX-2 表达，但效力显着不同（亚油酸 > 油酸 > 棕榈油酸），与每种不饱和 FFA 对棕榈酸诱发的细胞内信号（包括 p38、JNK、ERK1/2 MAPK 和 PKC theta，以及 I kappa B 降解）的抑制特性高度相关。此外，我们的数据表明，PPAR 几乎不参与不饱和 FFA 对棕榈酸酯诱导的 COX-2 表达的保护作用。没有检测到 COX-2 活性增加对棕榈酸诱导的胰岛素抵抗产生直接影响，至少在胰岛素反应性 Akt 磷酸化和 GLUT4 易位方面是如此。总而言之，我们的数据为 FFA 诱导骨骼肌中 COX-2 表达的分子机制提供了新的见解，并提出了这样的可能性：在骨骼肌细胞中，COX-2 及其产物前列腺素可能在由 FFA 升高引起的复杂炎症反应中发挥重要作用，例如在糖尿病状态下。
Kadotani A, Tsuchiya Y, Hatakeyama H, Katagiri H, Kanzaki M. Different impacts of saturated and unsaturated free fatty acids on COX-2 expression in C2C12 myotubes. Am J Physiol Endocrinol Metab 297: E1291-E1303, 2009. First published September 15, 2009; doi:10.1152/ajpendo.00293.2009.-In skeletal muscle, saturated free fatty acids (FFAs) act as proinflammatory stimuli, and cyclooxygenase-2 (COX-2) is a pro/anti-inflammatory enzyme induced at sites of inflammation, which contributes to prostaglandin production. However, little is known about the regulation of COX-2 expression and its responses to FFAs in skeletal muscle. Herein, we examined the effects of saturated and unsaturated FFAs, including a recently identified lipokine (lipid hormone derived from adipocytes), palmitoleate, on COX-2 expression in C2C12 myotubes as a skeletal muscle model. Exposure of myotubes to saturated FFAs [palmitate (16:0) and stearate (18:0)], but not to unsaturated FFAs [palmitoleate (16:1), oleate (18:1), and linoleate (18:2)], led to a slow-onset induction of COX-2 expression and subsequent prostaglandin E-2 production via mechanisms involving the p38 MAPK and NF-kappa B but not the PKC theta signaling cascades. Pharmacological modulation of mitochondrial oxidative function failed to interfere with COX-2 expression, suggesting the mitochondrial overload/excessive beta-oxidation contribution to this event to be minimal. On the contrary, unsaturated FFAs appeared to effectively antagonize palmitate-induced COX-2 expression with markedly different potencies (linoleate > oleate > palmitoleate), being highly associated with the suppressive profile of each unsaturated FFA toward palmitate-evoked intracellular signals, including p38, JNK, ERK1/2 MAPKs, and PKC theta, as well as I kappa B degradation. In addition, our data suggest little involvement of PPAR in the protective actions of unsaturated FFAs against palmitate-induced COX-2 expression. No direct contribution of the increased COX-2 activity in generating palmitate-induced insulin resistance was detected, at least in terms of insulin-responsive Akt phosphorylation and GLUT4 translocation. Taken together, our data provide a novel insight into the molecular mechanisms responsible for the FFA-induced COX-2 expression in skeletal muscle and raise the possibility that, in skeletal myocytes, COX-2 and its product prostaglandins may play an important role in the complex inflammation responses caused by elevated FFAs, for example, in the diabetic state.