PMID- 23832089
OWN - NLM
STAT- MEDLINE
DCOM- 20131101
LR  - 20211203
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 19
IP  - 8
DP  - 2013 Aug
TI  - Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by 
      decreasing mTorc1 stability.
PG  - 1054-60
LID - 10.1038/nm.3259 [doi]
AB  - Increased hepatic lipid content is an early correlate of insulin resistance and 
      can be caused by nutrient-induced activation of mammalian target of rapamycin 
      (mTor). This activation of mTor increases basal Akt activity, leading to a 
      self-perpetuating lipogenic cycle. We have previously shown that the 
      developmental Notch pathway has metabolic functions in adult mouse liver. Acute 
      or chronic inhibition of Notch dampens hepatic glucose production and increases 
      Akt activity and may therefore be predicted to increase hepatic lipid content. 
      Here we now show that constitutive liver-specific ablation of Notch signaling, or 
      its acute inhibition with a decoy Notch1 receptor, prevents hepatosteatosis by 
      blocking mTor complex 1 (mTorc1) activity. Conversely, Notch gain of function 
      causes fatty liver through constitutive activation of mTorc1, an effect that is 
      reversible by treatment with rapamycin. We demonstrate that Notch signaling 
      increases mTorc1 complex stability, augmenting mTorc1 function and sterol 
      regulatory element binding transcription factor 1c (Srebp1c)-mediated 
      lipogenesis. These data identify Notch as a therapeutically actionable branch 
      point of metabolic signaling at which Akt activation in the liver can be 
      uncoupled from hepatosteatosis.
FAU - Pajvani, Utpal B
AU  - Pajvani UB
AD  - Department of Medicine, Columbia University, New York, New York, USA. 
      up2104@columbia.edu
FAU - Qiang, Li
AU  - Qiang L
FAU - Kangsamaksin, Thaned
AU  - Kangsamaksin T
FAU - Kitajewski, Jan
AU  - Kitajewski J
FAU - Ginsberg, Henry N
AU  - Ginsberg HN
FAU - Accili, Domenico
AU  - Accili D
LA  - eng
GR  - DK63608/DK/NIDDK NIH HHS/United States
GR  - HL062454/HL/NHLBI NIH HHS/United States
GR  - R01 HL062454/HL/NHLBI NIH HHS/United States
GR  - DK093604/DK/NIDDK NIH HHS/United States
GR  - DK57539/DK/NIDDK NIH HHS/United States
GR  - R01 DK057539/DK/NIDDK NIH HHS/United States
GR  - P30 DK026687/DK/NIDDK NIH HHS/United States
GR  - R01 HL112626/HL/NHLBI NIH HHS/United States
GR  - K08 DK093604/DK/NIDDK NIH HHS/United States
GR  - P30 DK063608/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130707
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Immunoglobulin J Recombination Signal Sequence-Binding Protein)
RN  - 0 (Insulin)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Rbpj protein, mouse)
RN  - 0 (Receptors, Notch)
RN  - 0 (Triglycerides)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - Nat Med. 2013 Aug;19(8):969-71. PMID: 23921741
MH  - Animals
MH  - Blotting, Western
MH  - Body Weight/drug effects
MH  - Cell Line, Tumor
MH  - Diet, High-Fat
MH  - Enzyme Activation/drug effects
MH  - Fatty Liver/metabolism/pathology
MH  - Gene Expression Regulation/drug effects
MH  - HEK293 Cells
MH  - Humans
MH  - Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism
MH  - Insulin/pharmacology
MH  - Insulin Resistance
MH  - *Lipid Metabolism/drug effects/genetics
MH  - Lipogenesis/drug effects/genetics
MH  - Liver/drug effects/metabolism
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Multiprotein Complexes/*metabolism
MH  - Protein Stability/drug effects
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Receptors, Notch/*antagonists & inhibitors/metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Triglycerides/metabolism
PMC - PMC3737382
MID - NIHMS464428
COIS- Competing financial interest statement The Authors declare that they have no 
      competing financial interest in the work described.
EDAT- 2013/07/09 06:00
MHDA- 2013/11/02 06:00
PMCR- 2014/02/01
CRDT- 2013/07/09 06:00
PHST- 2013/01/24 00:00 [received]
PHST- 2013/04/04 00:00 [accepted]
PHST- 2013/07/09 06:00 [entrez]
PHST- 2013/07/09 06:00 [pubmed]
PHST- 2013/11/02 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - nm.3259 [pii]
AID - 10.1038/nm.3259 [doi]
PST - ppublish
SO  - Nat Med. 2013 Aug;19(8):1054-60. doi: 10.1038/nm.3259. Epub 2013 Jul 7.