mTORC1 activation is not sufficient to suppress hepatic PPARα signaling or ketogenesis.
mTORC1 activation is not sufficient to suppress hepatic PPARα signaling or ketogenesis.
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DOI：
10.1016/j.jbc.2021.100884
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Wolfgang MJ
中科院分区：
文献类型：
--
作者：
Selen ES;Wolfgang MJ
雷帕霉素的机制靶点（mTOR）通常被认为是细胞代谢的主要调节因子，可以整合生长因子和营养信号。禁食通过结节性硬化症复合体（TSC）的活性抑制肝脏mTORC1活性，TSC是mTORC1的负调节因子，从而抑制合成代谢。肝脏中TSC1的缺失即使在禁食期间也会使肝脏处于合成代谢状态，这被认为可以调节过氧化物酶体增殖激活受体α (PPARα)信号传导和酮生成，但这种调节的分子决定因素尚不清楚。在这里，我们研究了通过肝脏特异性缺失TSC1 （TSC1L−/−）激活小鼠的mTORC1复合物是否足以抑制PPARα信号传导，从而抑制禁食状态下的生酮。我们发现，在禁食状态下，mTORC1的激活不足以抑制ppar α-应答基因或酮生。此外，我们研究了在禁食状态下由mTORC1复合物激活介导的合成代谢程序的激活是否可以抑制具有肝脏特异性缺陷的小鼠使用肉碱棕榈酰基转移酶2 （Cpt2L - / -）氧化线粒体长链脂肪酸的强大分解代谢程序和增强PPARα转录反应。我们生成了Cpt2L−/−；结果表明，通过删除TSC1激活mTORC1不能抑制Cpt2L - / -小鼠的分解代谢ppar α-介导的表型。这些数据表明，通过删除TSC1激活mTORC1并不足以抑制禁食后的PPARα转录程序或酮生成。
The mechanistic target of rapamycin (mTOR) is often referred to as a master regulator of the cellular metabolism that can integrate the growth factor and nutrient signaling. Fasting suppresses hepatic mTORC1 activity via the activity of the tuberous sclerosis complex (TSC), a negative regulator of mTORC1, to suppress anabolic metabolism. The loss of TSC1 in the liver locks the liver in a constitutively anabolic state even during fasting, which was suggested to regulate peroxisome proliferator-activated receptor alpha (PPARα) signaling and ketogenesis, but the molecular determinants of this regulation are unknown. Here, we examined if the activation of the mTORC1 complex in mice by the liver-specific deletion of TSC1 (TSC1L−/−) is sufficient to suppress PPARα signaling and therefore ketogenesis in the fasted state. We found that the activation of mTORC1 in the fasted state is not sufficient to repress PPARα-responsive genes or ketogenesis. Furthermore, we examined whether the activation of the anabolic program mediated by mTORC1 complex activation in the fasted state could suppress the robust catabolic programming and enhanced PPARα transcriptional response of mice with a liver-specific defect in mitochondrial long-chain fatty acid oxidation using carnitine palmitoyltransferase 2 (Cpt2L−/−) mice. We generated Cpt2L−/−; Tsc1L−/− double-KO mice and showed that the activation of mTORC1 by deletion of TSC1 could not suppress the catabolic PPARα-mediated phenotype of Cpt2L−/− mice. These data demonstrate that the activation of mTORC1 by the deletion of TSC1 is not sufficient to suppress a PPARα transcriptional program or ketogenesis after fasting.
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影响因子：
29
作者：
Yecies JL;Zhang HH;Menon S;Liu S;Yecies D;Lipovsky AI;Gorgun C;Kwiatkowski DJ;Hotamisligil GS;Lee CH;Manning BD
通讯作者：
Manning BD
影响因子：
8.8
作者：
Iroz A;Montagner A;Benhamed F;Levavasseur F;Polizzi A;Anthony E;Régnier M;Fouché E;Lukowicz C;Cauzac M;Tournier E;Do-Cruzeiro M;Daujat-Chavanieu M;Gerbal-Chalouin S;Fauveau V;Marmier S;Burnol AF;Guilmeau S;Lippi Y;Girard J;Wahli W;Dentin R;Guillou H;Postic C
通讯作者：
Postic C
影响因子：
64.5
作者：
Perry RJ;Camporez JG;Kursawe R;Titchenell PM;Zhang D;Perry CJ;Jurczak MJ;Abudukadier A;Han MS;Zhang XM;Ruan HB;Yang X;Caprio S;Kaech SM;Sul HS;Birnbaum MJ;Davis RJ;Cline GW;Petersen KF;Shulman GI
通讯作者：
Shulman GI
影响因子：
29
作者：
Badman, Michael K.;Pissios, Pavlos;Maratos-Flier, Eleftheria
通讯作者：
Maratos-Flier, Eleftheria
影响因子：
13.5
作者：
Kim, KyeongJin;Pyo, Suhkneung;Um, Sung Hee
通讯作者：
Um, Sung Hee