PMID- 34146544
OWN - NLM
STAT- MEDLINE
DCOM- 20210825
LR  - 20210825
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 297
IP  - 1
DP  - 2021 Jul
TI  - mTORC1 activation is not sufficient to suppress hepatic PPARalpha signaling or 
      ketogenesis.
PG  - 100884
LID - S0021-9258(21)00684-0 [pii]
LID - 10.1016/j.jbc.2021.100884 [doi]
LID - 100884
AB  - 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 (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. 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 PPARalpha transcriptional response of 
      mice with a liver-specific defect in mitochondrial long-chain fatty acid 
      oxidation using carnitine palmitoyltransferase 2 (Cpt2(L-/-)) mice. We generated 
      Cpt2(L-/-); Tsc1(L-/-) double-KO 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 after fasting.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Selen, Ebru S
AU  - Selen ES
AD  - Department of Biological Chemistry, The Johns Hopkins University School of 
      Medicine, Baltimore, Maryland, USA.
FAU - Wolfgang, Michael J
AU  - Wolfgang MJ
AD  - Department of Biological Chemistry, The Johns Hopkins University School of 
      Medicine, Baltimore, Maryland, USA; Department of Pharmacology and Molecular 
      Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 
      USA. Electronic address: mwolfga1@jhmi.edu.
LA  - eng
GR  - R01 DK116746/DK/NIDDK NIH HHS/United States
GR  - R01 DK120530/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210617
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
MH  - Animals
MH  - Carnitine O-Palmitoyltransferase/genetics/metabolism
MH  - Fasting/*metabolism
MH  - Gene Deletion
MH  - Liver/*metabolism
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism
MH  - Phenotype
MH  - *Signal Transduction
MH  - Tuberous Sclerosis Complex 1 Protein/*genetics/metabolism
PMC - PMC8294577
OTO - NOTNLM
OT  - carnitine palmitoyltransferase 2 (Cpt2)
OT  - fatty acid oxidation
OT  - ketogenesis
OT  - mTOR
OT  - metabolism
OT  - peroxisome proliferator-activated receptor alpha (PPARalpha)
OT  - beta-hydroxybutyrate (betaHB)
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2021/06/20 06:00
MHDA- 2021/08/26 06:00
PMCR- 2021/06/17
CRDT- 2021/06/19 20:09
PHST- 2021/04/28 00:00 [received]
PHST- 2021/06/04 00:00 [revised]
PHST- 2021/06/15 00:00 [accepted]
PHST- 2021/06/20 06:00 [pubmed]
PHST- 2021/08/26 06:00 [medline]
PHST- 2021/06/19 20:09 [entrez]
PHST- 2021/06/17 00:00 [pmc-release]
AID - S0021-9258(21)00684-0 [pii]
AID - 100884 [pii]
AID - 10.1016/j.jbc.2021.100884 [doi]
PST - ppublish
SO  - J Biol Chem. 2021 Jul;297(1):100884. doi: 10.1016/j.jbc.2021.100884. Epub 2021 
      Jun 17.