Takashima Mototsugu, Ogawa Wataru, Emi Aki, Kasuga Masato
Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Kobe J Med Sci. 2009 Nov 24;55(2):E45-52.
The transcription factor sterol regulatory element-binding protein 1c (SREBP1c) plays an important role in the regulation of fatty acid metabolism in the liver. Although the importance of phosphoinositide 3-kinase in the regulation of SREBP1c expression is widely accepted, the role of mammalian target of rapamycin (mTOR) in such regulation has remained unclear. We have now shown that the insulin-induced increase in the abundance of SREBP1c mRNA in cultured AML12 mouse hepatocytes was largely abolished by LY294002, an inhibitor of phosphoinositide 3-kinase, but was reduced only slightly by rapamycin, an inhibitor of mTOR. Forced expression of a constitutively active form of Akt containing a myristoylation signal sequence (MyrAkt) in these cells with the use of an adenoviral vector resulted in the phosphorylation of p70 S6 kinase, a downstream target of mTOR signaling, and this effect was inhibited by rapamycin. MyrAkt also increased the abundance of SREBP1c mRNA and protein as well as the expression of the SREBP1c target genes for fatty acid synthase and stearoyl-CoA desaturase 1. These effects of MyrAkt were also markedly inhibited by LY294002 and by rapamycin. These results thus suggest that mTOR signaling plays a major role in Akt-mediated up-regulation of SREBP1c expression but that it plays only a minor role in insulin-induced expression of this transcription factor.
转录因子固醇调节元件结合蛋白1c（SREBP1c）在肝脏脂肪酸代谢的调节中起重要作用。尽管磷酸肌醇3激酶在调节SREBP1c表达中的重要性已被广泛认可，但雷帕霉素靶蛋白（mTOR）在这种调节中的作用仍不清楚。我们现在已经表明，在培养的AML12小鼠肝细胞中，胰岛素诱导的SREBP1c mRNA丰度增加在很大程度上被磷酸肌醇3激酶抑制剂LY294002消除，但仅被mTOR抑制剂雷帕霉素轻微降低。使用腺病毒载体在这些细胞中强制表达含有肉豆蔻酰化信号序列的组成型活性形式的Akt（MyrAkt）导致mTOR信号传导的下游靶点p70 S6激酶磷酸化，并且这种作用被雷帕霉素抑制。MyrAkt还增加了SREBP1c mRNA和蛋白质的丰度以及脂肪酸合酶和硬脂酰辅酶A去饱和酶1的SREBP1c靶基因的表达。MyrAkt的这些作用也被LY294002和雷帕霉素显著抑制。因此，这些结果表明，mTOR信号传导在Akt介导的SREBP1c表达上调中起主要作用，但在胰岛素诱导的该转录因子表达中仅起次要作用。
