| First Author | Selen ES | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 1 | Pages | 100884 |
| PubMed ID | 34146544 | Mgi Jnum | J:343891 |
| Mgi Id | MGI:6720171 | Doi | 10.1016/j.jbc.2021.100884 |
| Citation | Selen ES, et al. (2021) mTORC1 Activation is Not Sufficient to Suppress Hepatic PPARalpha Signaling or Ketogenesis. J Biol Chem :100884 |
| abstractText | The mechanistic target of rapamycin (mTOR) is often referred to as a master regulator of cellular metabolism that can integrate growth factor and nutrient signaling. Fasting suppresses hepatic mTORC1 activity via the activity of the Tuberous Sclerosis Complex (TSC), a negative regulator of mTORC1, in order 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 PPARalpha 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 (TSC1(L-/-)) is sufficient to suppress PPARalpha signaling and therefore ketogenesis in the fasted state. We found that the activation of mTORC1 in the fasted state is not sufficient to repress PPARalpha-responsive genes or ketogenesis. Further, 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 PPARalpha transcriptional response of mice with a liver-specific defect in mitochondrial long-chain fatty acid oxidation using Cpt2(L-/-) mice. We generated liver-specific Cpt2(L-/-); Tsc1(L-/-) double knockout mice and showed that the activation of mTORC1 by deletion of TSC1 could not suppress the catabolic PPARalpha-mediated phenotype of Cpt2(L-/-) mice. These data demonstrate that the activation of mTORC1 by the deletion of TSC1 is not sufficient to suppress a PPARalpha transcriptional program or ketogenesis following fasting. |
