Tumor necrosis factor-like weak inducer of apoptosis attenuates the action of insulin in hepatocytes
Tumor necrosis factor-like weak inducer of apoptosis attenuates the action of insulin in hepatocytes
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DOI：
10.1210/en.2007-1119
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发表时间：
2008-04-01
期刊：
影响因子：
4.8
通讯作者：
Xia, Pu
中科院分区：
文献类型：
--
作者：
Feng, Feng;Wang, Lijun;Xia, Pu
TNF-like weak inducer of apoptosis （TWEAK）是TNF超家族中一个相对较新的成员，是一种重要的免疫/炎症调节剂，具有不同于该超家族其他成员的功能特性。我们在此报道，TWEAK通过抑制早期胰岛素受体（IR）信号事件和胰岛素的下游作用，诱导人肝癌细胞系（Huh7和HepG2）和原代大鼠肝细胞的细胞胰岛素抵抗。TWEAK以浓度和时间依赖的方式显著抑制胰岛素诱导的Akt磷酸化。这种抑制作用的发生机制涉及TWEAK受体Fn14和典型和非典型核因子κ B信号通路的激活。此外，TWEAK显著抑制IR β自磷酸化和IR底物-1激活，同时增加IR底物-1丝氨酸磷酸化。此外，胰岛素诱导的肝细胞糖异生酶基因表达的降低和糖原合成的增加在TWEAK治疗下明显减弱。因此，这些发现不仅揭示了TWEAK/Fn14的一种新的病理生理功能，还揭示了一个可能参与肝细胞胰岛素抵抗发展的新参与者。
TNF-like weak inducer of apoptosis (TWEAK), a relatively new member of the TNF superfamily, is an important immune/ inflammatory regulator that has different functional properties from that of other members of this superfamily. We report herein that TWEAK induces cellular insulin resistance in both human hepatocellular carcinoma cell lines (Huh7 and HepG2) and primary rat hepatocytes by inhibiting both early insulin receptor (IR) signaling events and the downstream actions of insulin. TWEAK profoundly inhibited insulin-induced Akt phosphorylation in both a concentration- and time-dependent manner. This inhibitory effect occurred via mechanisms that involved the TWEAK receptor Fn14 and the activation of the canonical and noncanonical nuclear factor-kappa B signaling pathways. Furthermore, TWEAK significantly inhibited IR beta auto-phosphorylation and IR substrate-1 activation, with concomitant increases in serine phosphorylation of IR substrate-1. Moreover, insulin-induced reduction of gluconeogenic enzyme gene expression and increases in glycogen synthesis in hepatocytes were significantly attenuated by TWEAK treatment. Therefore, these findings not only reveal a novel pathophysiological function of TWEAK/Fn14 but also uncover a new player that may contribute to the development of cellular insulin resistance in hepatocytes.