Hepatic mTORC2 Activates Glycolysis and Lipogenesis through Akt, Glucokinase, and SREBP1c
Hepatic mTORC2 Activates Glycolysis and Lipogenesis through Akt, Glucokinase, and SREBP1c
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DOI：
10.1016/j.cmet.2012.03.015
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发表时间：
2012-05-02
期刊：
影响因子：
29
通讯作者：
Hall, Michael N.
中科院分区：
文献类型：
--
作者：
Hagiwara, Asami;Cornu, Marion;Hall, Michael N.
雷帕霉素靶蛋白复合物2（mTORC2）在胰岛素/胰岛素样生长因子1（IGF1）的作用下，使AGC激酶家族成员（包括Akt、SGK1和PKC）磷酸化并激活。肝脏是胰岛素介导的代谢调节的关键器官。为了评估肝脏mTORC2的作用，我们构建了肝脏特异性rictor基因敲除（LiRiKO）小鼠。喂食后的LiRiKO小鼠肝脏中Akt的丝氨酸473位点磷酸化缺失，葡萄糖激酶和SREBP1c活性降低，导致持续性糖异生，糖酵解和脂肪生成受损，这表明mTORC2缺陷的肝脏无法感知饱腹感。这些肝脏特异性缺陷导致全身性高血糖、高胰岛素血症和低脂血症。在mTORC2缺陷的肝细胞中表达组成性激活的Akt2可恢复葡萄糖通量和脂肪生成，而葡萄糖激酶的过表达可挽救葡萄糖通量但不能挽救脂肪生成。因此，mTORC2通过胰岛素诱导的Akt信号传导调节肝脏葡萄糖和脂质代谢，以控制全身代谢稳态。这些发现对以mTORC2为靶点的新兴药物疗法具有启示意义。
Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRikO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2.