Ryu Dongryeol, Oh Kyoung-Jin, Jo Hee-Yeon, Hedrick Susan, Kim Yo-Na, Hwang Yu-Jin, Park Tae-Sik, Han Joong-Soo, Choi Cheol Soo, Montminy Marc, Koo Seung-Hoi
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Korea.
Cell Metab. 2009 Mar;9(3):240-51. doi: 10.1016/j.cmet.2009.01.007.
TORC2 is a major transcriptional coactivator for hepatic glucose production. Insulin impedes gluconeogenesis by inhibiting TORC2 via SIK2-dependent phosphorylation at Ser171. Interruption of this process greatly perturbs hepatic glucose metabolism, thus promoting hyperglycemia in rodents. Here, we show that hyperactivation of TORC2 would exacerbate insulin resistance by enhancing expression of LIPIN1, a mammalian phosphatidic acid phosphatase for diacylglycerol (DAG) synthesis. Diet-induced or genetic obesity increases LIPIN1 expression in mouse liver, and TORC2 is responsible for its transcriptional activation. While overexpression of LIPIN1 disturbs hepatic insulin signaling, knockdown of LIPIN1 ameliorates hyperglycemia and insulin resistance by reducing DAG and PKCvarepsilon activity in db/db mice. Finally, TORC2-mediated insulin resistance is partially rescued by concomitant knockdown of LIPIN1, confirming the critical role of LIPIN1 in the perturbation of hepatic insulin signaling. These data propose that dysregulation of TORC2 would further exaggerate insulin resistance and promote type 2 diabetes in a LIPIN1-dependent manner.
TORC2是肝脏葡萄糖生成的主要转录共激活因子。胰岛素通过SIK2依赖的Ser171位点磷酸化抑制TORC2，从而阻碍糖异生。这一过程的中断会极大地扰乱肝脏葡萄糖代谢，进而导致啮齿动物出现高血糖。在此，我们表明TORC2的过度激活会通过增强LIPIN1的表达来加剧胰岛素抵抗，LIPIN1是一种用于合成二酰甘油（DAG）的哺乳动物磷脂酸磷酸酶。饮食诱导或基因肥胖会增加小鼠肝脏中LIPIN1的表达，而TORC2负责其转录激活。虽然LIPIN1的过表达会扰乱肝脏胰岛素信号，但敲低LIPIN1可通过降低db/db小鼠体内的DAG和PKCε活性来改善高血糖和胰岛素抵抗。最后，同时敲低LIPIN1可部分挽救TORC2介导的胰岛素抵抗，证实了LIPIN1在扰乱肝脏胰岛素信号中的关键作用。这些数据表明，TORC2的失调会以LIPIN1依赖的方式进一步加剧胰岛素抵抗并促进2型糖尿病。
