Acylcarnitines activate proinflammatory signaling pathways
Acylcarnitines activate proinflammatory signaling pathways
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DOI：
10.1152/ajpendo.00656.2013
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发表时间：
2014-06-15
影响因子：
5.1
通讯作者：
Hwang, Daniel H.
中科院分区：
文献类型：
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作者：
Rutkowsky, Jennifer M.;Knotts, Trina A.;Hwang, Daniel H.
线粒体中脂肪酸的不完全β-氧化是胰岛素抵抗和2型糖尿病（T2 DM）的特征。先前的研究表明，中链和长链酰基肉毒碱（不完全β-氧化的副产物）的血浆浓度在T2 DM和胰岛素抵抗中升高。在以前的研究中，我们报道了C12-或C14-肉毒碱的混合D，L异构体在RAW 264.7细胞中诱导NF-κ B-荧光素酶报告基因，表明促炎途径的潜在激活。在这里，我们确定了生理相关的L-酰基肉毒碱是否激活经典的促炎信号通路，以及这些结果是否涉及模式识别受体（PRR）相关的通路。酰基肉毒碱诱导环氧化酶-2在RAW 264.7细胞中以链长度依赖的方式表达。L-C14肉毒碱（5-25 μ M），用作代表性的酰基肉毒碱，刺激促炎细胞因子的表达和分泌，以剂量依赖性的方式。此外，L-C14肉毒碱诱导JNK和ERK的磷酸化，JNK和ERK是包括PRR在内的许多促炎信号通路的共同下游组分。MyD 88是PRR信号传导和炎症的关键辅因子，MyD 88的敲低减弱了酰基肉毒碱的促炎作用。虽然这些结果指出PRR的潜在参与，但L-C14肉毒碱促进了缺乏Toll样受体（TLR）2和-4的人上皮细胞（HCT-116）的IL-8分泌，并且在TLR过表达细胞模型中不激活报告构建体。因此，酰基肉毒碱具有激活炎症的潜力，但涉及的特定分子和组织靶点仍有待鉴定。
Incomplete beta-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium-and long-chain acylcarnitines (by-products of incomplete beta-oxidation) are elevated in T2DM and insulin resistance. In a previous study, we reported that mixed D, L isomers of C12- or C14-carnitine induced an NF-kappa B-luciferase reporter gene in RAW 264.7 cells, suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant L-acylcarnitines activate classical proinflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of cyclooxygenase-2 in a chain length-dependent manner in RAW 264.7 cells. L-C14 carnitine (5-25 mu M), used as a representative acylcarnitine, stimulated the expression and secretion of proinflammatory cytokines in a dose-dependent manner. Furthermore, L-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many proinflammatory signaling pathways including PRRs. Knockdown of MyD88, a key cofactor in PRR signaling and inflammation, blunted the proinflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, L-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking Toll-like receptors (TLR) 2 and -4, and did not activate reporter constructs in TLR overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified.