Department of Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Biochem Biophys Res Commun. 2011 Aug 26;412(2):197-202. doi: 10.1016/j.bbrc.2011.07.038. Epub 2011 Jul 22.
The transcription factor sterol regulatory element-binding protein 1c (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.
固醇调节元件结合蛋白 1c（SREBP1c）转录因子在肝脏脂肪酸代谢的控制中发挥重要作用。有证据表明，雷帕霉素靶蛋白（mTOR）复合物 1（mTORC1）有助于调节 SREBP1c 的表达，但 mTORC1 的下游信号仍然不清楚。我们现在已经表明，富含支链氨基酸的培养基以一种对 rapamycin（mTORC1 的药理学抑制剂）和针对 mTORC1 的下游效应物 S6 激酶 1（S6K1）的短发夹 RNA（shRNA）都敏感的方式刺激培养的肝细胞中 SREBP1c 基因的表达。肥胖 db/db 小鼠肝脏中 S6K1 的磷酸化增加。此外，使用编码 S6K1 shRNA 的腺病毒载体在 db/db 小鼠中耗尽肝 S6K1 导致 SREBP1c 基因在肝脏中的表达下调以及肝甘油三酯含量和血清甘油三酯浓度降低。这些结果表明 S6K1 既在培养的肝细胞中又在小鼠肝脏中调节 SREBP1c 的表达，并且肝 S6K1 活性的增加至少部分导致肥胖诱导的肝脂肪变性和高甘油三酯血症的发病机制。
