Role of S6K1 in regulation of SREBP1c expression in the liver
Role of S6K1 in regulation of SREBP1c expression in the liver
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DOI：
10.1016/j.bbrc.2011.07.038
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发表时间：
2011-08-26
影响因子：
3.1
通讯作者：
Kasuga, Masato
中科院分区：
文献类型：
--
作者：
Li, Shuying;Ogawa, Wataru;Kasuga, Masato
转录因子固醇调节元件结合蛋白1c（SREBP 1c）在肝脏脂肪酸代谢的控制中起重要作用。有证据表明，哺乳动物雷帕霉素靶蛋白复合物1（mTOR 1）有助于调节SREBP 1c的表达，但mTOR 1下游的信号转导仍不清楚。我们现在已经表明，培养基中富含支链氨基酸刺激SREBP 1c基因在培养的肝细胞中的表达，其方式对雷帕霉素（mTORC 1的药理学抑制剂）和对S6激酶1（S6 K1）（mTORC 1的下游效应子）特异性的短发夹RNA（shRNA）敏感。肥胖db/db小鼠肝脏中S6 K1磷酸化增加。此外，使用编码S6 K1 shRNA的腺病毒载体在db/db小鼠中消耗肝脏S6 K1导致肝脏中SREBP 1c基因表达下调以及肝脏甘油三酯含量和血清甘油三酯浓度降低。因此，这些结果表明，S6 K1调节SREBP 1c在培养的肝细胞和小鼠肝脏中的表达，并且S6 K1的肝活性增加至少部分地导致肥胖诱导的肝脂肪变性和高脂血症的发病机制。(C)2011 Elsevier Inc. All rights reserved.
The transcription factor sterol regulatory element-binding protein lc (SREBP1c) plays an important role in the control of fatty acid metabolism in the liver. Evidence suggests that mammalian target of rapamycin (mTOR) complex 1 (mTORC1) contributes to the regulation of SREBP1c expression, but signaling downstream of mTORC1 remains unclear. We have now shown that medium rich in branched-chain amino acids stimulates expression of the SREBP1c gene in cultured hepatocytes in a manner sensitive both to rapamycin, a pharmacological inhibitor of mTORC1, and to a short hairpin RNA (shRNA) specific for S6 kinase 1 (S6K1), a downstream effector of mTORC1. The phosphorylation of S6K1 was increased in the liver of obese db/db mice. Furthermore, depletion of hepatic S6K1 in db/db mice with the use of an adenovirus vector encoding S6K1 shRNA resulted in down-regulation of SREBP1c gene expression in the liver as well as a reduced hepatic triglyceride content and serum triglyceride concentration. These results thus suggest that S6K1 regulates SREBP1c expression both in cultured hepatocytes and in mouse liver, and that increased hepatic activity of S6K1 contributes at least in part to the pathogenesis of obesity-induced hepatic steatosis and hypertriglyceridemia. (C) 2011 Elsevier Inc. All rights reserved.