Branched-Chain Amino Acid Negatively Regulates KLF15 Expression via PI3K-AKT Pathway.
Branched-Chain Amino Acid Negatively Regulates KLF15 Expression via PI3K-AKT Pathway.
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支链氨基酸通过 PI3K-AKT 途径负调节 KLF15 表达
DOI：
10.3389/fphys.2017.00853
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发表时间：
2017
影响因子：
4
通讯作者：
Sun H
中科院分区：
文献类型：
--
作者：
Liu Y;Dong W;Shao J;Wang Y;Zhou M;Sun H
最近的研究已经将支链氨基酸（BCAA）与许多代谢疾病联系起来。然而，支链氨基酸在代谢调节中作用的分子基础仍有待建立。KLF 15（Krüppel样因子15）是一种转录因子，是血糖、脂质和氨基酸代谢的主要调节因子。在本研究中，我们发现高浓度的BCAA抑制了KLF 15的表达，而BCAA饥饿则诱导了KLF 15的表达，这表明KLF 15的表达受BCAA的负调控。有趣的是，BCAA饥饿诱导了PI 3 K-AKT信号。PI 3 K和AKT抑制剂可阻断BCAA饥饿诱导的KLF 15表达，表明PI 3 K-AKT信号通路的激活介导了KLF 15的诱导。BCAA在转录水平调控KLF 15的表达，而在转录后水平不调控。然而，BCAA饥饿未能增加KLF 15启动子驱动的荧光素酶表达，表明KLF 15启动子活性不受BCAA直接控制。最后，禁食减少了小鼠体内BCAA的丰度，KLF 15的表达在肌肉和白色脂肪组织中显著诱导，但在肝脏中没有。总之，这些数据表明BCAA负调控KLF 15表达，表明BCAA在代谢调节中的多种功能的新分子机制。
Recent studies have linked branched-chain amino acid (BCAA) with numerous metabolic diseases. However, the molecular basis of BCAA's roles in metabolic regulation remains to be established. KLF15 (Krüppel-like factor 15) is a transcription factor and master regulator of glycemic, lipid, and amino acids metabolism. In the present study, we found high concentrations of BCAA suppressed KLF15 expression while BCAA starvation induced KLF15 expression, suggesting KLF15 expression is negatively controlled by BCAA.Interestingly, BCAA starvation induced PI3K-AKT signaling. KLF15 induction by BCAA starvation was blocked by PI3K and AKT inhibitors, indicating the activation of PI3K-AKT signaling pathway mediated the KLF15 induction. BCAA regulated KLF15 expression at transcriptional level but not post-transcriptional level. However, BCAA starvation failed to increase the KLF15-promoter-driven luciferase expression, suggesting KLF15 promoter activity was not directly controlled by BCAA. Finally, fasting reduced BCAA abundance in mice and KLF15 expression was dramatically induced in muscle and white adipose tissue, but not in liver. Together, these data demonstrated BCAA negatively regulated KLF15 expression, suggesting a novel molecular mechanism underlying BCAA's multiple functions in metabolic regulation.
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影响因子：
8.8
作者：
Takeuchi Y;Yahagi N;Aita Y;Murayama Y;Sawada Y;Piao X;Toya N;Oya Y;Shikama A;Takarada A;Masuda Y;Nishi M;Kubota M;Izumida Y;Yamamoto T;Sekiya M;Matsuzaka T;Nakagawa Y;Urayama O;Kawakami Y;Iizuka Y;Gotoda T;Itaka K;Kataoka K;Nagai R;Kadowaki T;Yamada N;Lu Y;Jain MK;Shimano H
通讯作者：
Shimano H
DOI：
10.1126/science.aad2087
发表时间：
2016-01-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Saxton RA;Knockenhauer KE;Wolfson RL;Chantranupong L;Pacold ME;Wang T;Schwartz TU;Sabatini DM
通讯作者：
Sabatini DM
DOI：
10.1016/j.bbrc.2003.07.012
发表时间：
2004-01-09
影响因子：
3.1
作者：
Meijer, AJ;Dubbelhuis, PF
通讯作者：
Dubbelhuis, PF
影响因子：
16.6
作者：
Han, Sean (Shuxin);Zhang, Rongli;Jain, Rajan;Shi, Hong;Zhang, Lilei;Zhou, Guangjin;Sangwung, Panjamaporn;Tugal, Derin;Atkins, G. Brandon;Prosdocimo, Domenick A.;Lu, Yuan;Han, Xiaonan;Tso, Patrick;Liao, Xudong;Epstein, Jonathan A.;Jain, Mukesh K.
通讯作者：
Jain, Mukesh K.
影响因子：
64.8
作者：
Dey P;Baddour J;Muller F;Wu CC;Wang H;Liao WT;Lan Z;Chen A;Gutschner T;Kang Y;Fleming J;Satani N;Zhao D;Achreja A;Yang L;Lee J;Chang E;Genovese G;Viale A;Ying H;Draetta G;Maitra A;Wang YA;Nagrath D;DePinho RA
通讯作者：
DePinho RA