Department of Nutrition and Food Hygiene and MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
J Biol Chem. 2013 Mar 29;288(13):9313-20. doi: 10.1074/jbc.M112.409409. Epub 2013 Feb 12.
In this study, we addressed the direct effect of leucine on insulin signaling. In investigating the associated mechanisms, we found that leucine itself does not activate the classical Akt- or ERK1/2 MAP kinase-dependent signaling pathways but can facilitate the insulin-induced phosphorylations of Akt(473) and ERK1/2 in a time- and dose-dependent manner in cultured hepatocytes. The leucine-facilitated insulin-induced phosphorylation of Akt at residue 473 was not affected by knocking down the key component of mTORC1 or -2 complexes but was blocked by inhibition of c-Src (PP2), PI3K (LY294002), Gαi protein (pertussis toxin or siRNA against Gαi1 gene, or β-arrestin 2 (siRNA)). Similarly, the leucine-facilitated insulin activation of ERK1/2 was also blunted by pertussis toxin. We further show that leucine facilitated the insulin-mediated suppression of glucose production and expression of key gluconeogenic genes in a Gαi1 protein-dependent manner in cultured primary hepatocytes. Together, these results show that leucine can directly facilitate insulin signaling through a Gαi protein-dependent intracellular signaling pathway. This is the first evidence showing that macronutrients like amino acid leucine can facilitate insulin signaling through G proteins directly.
在这项研究中，我们研究了亮氨酸对胰岛素信号的直接影响。在研究相关机制时，我们发现亮氨酸本身不会激活经典的 Akt-或 ERK1/2 MAP 激酶依赖性信号通路，但可以在培养的肝细胞中以时间和剂量依赖的方式促进胰岛素诱导的 Akt(473)和 ERK1/2 的磷酸化。亮氨酸促进 Akt 在残基 473 处的胰岛素诱导磷酸化不受 mTORC1 或 -2 复合物关键成分敲低的影响，但被 c-Src(PP2)、PI3K(LY294002)、Gαi 蛋白(百日咳毒素或针对 Gαi1 基因的 siRNA)或β-arrestin 2(siRNA)抑制。同样，亮氨酸促进胰岛素激活 ERK1/2 的作用也被百日咳毒素减弱。我们进一步表明，亮氨酸以 Gαi1 蛋白依赖性方式促进胰岛素介导的糖生成抑制和关键糖异生基因表达在培养的原代肝细胞中。总之，这些结果表明亮氨酸可以通过 G 蛋白依赖性细胞内信号通路直接促进胰岛素信号。这是第一个证明像氨基酸亮氨酸这样的大量营养素可以通过 G 蛋白直接促进胰岛素信号的证据。
