mTORC1 activation is not sufficient to suppress hepatic PPARα signaling or ketogenesis
| العنوان: | mTORC1 activation is not sufficient to suppress hepatic PPARα signaling or ketogenesis |
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| المؤلفون: | Ebru S. Selen, Michael J. Wolfgang |
| المصدر: | The Journal of Biological Chemistry |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Anabolism, mTORC1, Biochemistry, carnitine palmitoyltransferase 2 (Cpt2), Tuberous Sclerosis Complex 1 Protein, βHB, beta hydroxybutyrate, Mice, DKO, double-KO, Ketogenesis, Beta oxidation, fatty acid oxidation, TSC1L−/−, liver-specific deletion of TSC1, TGs, triglycerides, biology, Chemistry, mTOR, mechanistic target of rapamycin, Fasting, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Cell biology, Phenotype, Liver, mTOR, Peroxisome proliferator-activated receptor alpha, biological phenomena, cell phenomena, and immunity, Research Article, Signal Transduction, Mechanistic Target of Rapamycin Complex 1, Cpt2L−/−, liver-specific deletion of carnitine palmitoyltransferase 2, 03 medical and health sciences, Animals, β-hydroxybutyrate (βHB), Molecular Biology, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, PCA, principal component analysis, 030102 biochemistry & molecular biology, peroxisome proliferator-activated receptor alpha (PPARα), PPARα, peroxisome proliferator-activated receptor alpha, Carnitine O-Palmitoyltransferase, Catabolism, Cell Biology, ketogenesis, Mice, Inbred C57BL, 030104 developmental biology, biology.protein, TSC, tuberous sclerosis complex, metabolism, Gene Deletion |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da26170e74a36a230b9f59cc4986fc2cTest http://europepmc.org/articles/PMC8294577Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....da26170e74a36a230b9f59cc4986fc2c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
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