PMID- 21252047
OWN - NLM
STAT- MEDLINE
DCOM- 20111012
LR  - 20211203
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Linking)
VI  - 301
IP  - 2
DP  - 2011 Aug
TI  - Mammalian target of rapamycin mediates the angiogenic effects of leptin in human 
      hepatic stellate cells.
PG  - G210-9
LID - 10.1152/ajpgi.00047.2010 [doi]
AB  - Leptin modulates the angiogenic properties of hepatic stellate cells (HSC), but 
      the molecular mechanisms involved are poorly understood. We investigated the 
      pathways regulating hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial 
      growth factor (VEGF) in leptin-stimulated myofibroblastic HSC. Exposure to leptin 
      enhanced the phosphorylation of TSC2 on T1462 residues and of p70 S6 kinase and 
      the translational inhibitor 4E-binding protein-1, indicating the ability of 
      leptin to activate the mammalian target of rapamycin (mTOR) pathway. Similar 
      findings were observed when HSC were exposed to PDGF. Both leptin and PDGF 
      increased the expression of HIF-1alpha and VEGF in HSC. In the presence of rapamycin, 
      a specific mTOR inhibitor, leptin and PDGF were no longer able to activate mTOR, 
      and expression of VEGF was reduced, whereas HIF-1alpha abundance was not affected. 
      Moreover, knockdown of Raptor, a component of the mTORC1 complex, reduced the 
      ability of leptin to increase VEGF. mTOR was also necessary for leptin- and 
      PDGF-dependent increase in HSC migration. Leptin increased the generation of 
      reactive oxygen species in HSC, which was reduced by NADP(H) oxidase inhibitors. 
      Both N-acetyl cysteine and diphenylene iodonium, a NADP(H) inhibitor, inhibited 
      the expression of HIF-1alpha and VEGF stimulated by leptin or PDGF. Finally, 
      conditioned media from HSC treated with leptin or PDGF induced tube formation in 
      cultured human umbilical vein endothelial cells. In conclusion, in HSC exposed to 
      leptin or PDGF, increased expression of VEGF requires both activation of mTOR and 
      generation of reactive oxygen species via NADPH-oxidase. Induction of HIF-1alpha 
      requires NADP(H) oxidase but not mTOR activation.
FAU - Aleffi, Sara
AU  - Aleffi S
AD  - Dipartimento di Medicina Interna, University of Florence, Italy.
FAU - Navari, Nadia
AU  - Navari N
FAU - Delogu, Wanda
AU  - Delogu W
FAU - Galastri, Sara
AU  - Galastri S
FAU - Novo, Erica
AU  - Novo E
FAU - Rombouts, Krista
AU  - Rombouts K
FAU - Pinzani, Massimo
AU  - Pinzani M
FAU - Parola, Maurizio
AU  - Parola M
FAU - Marra, Fabio
AU  - Marra F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110120
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Leptin)
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Cell Line
MH  - Cell Movement/physiology
MH  - Hep G2 Cells
MH  - Hepatic Stellate Cells/metabolism/pathology/*physiology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism/physiology
MH  - Leptin/metabolism/*physiology
MH  - Liver/*blood supply
MH  - NADPH Oxidases/physiology
MH  - Neovascularization, Pathologic
MH  - Neovascularization, Physiologic
MH  - Phosphorylation
MH  - Platelet-Derived Growth Factor/physiology
MH  - Reactive Oxygen Species/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/chemistry
MH  - Signal Transduction/*physiology
MH  - TOR Serine-Threonine Kinases/*physiology
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/chemistry
MH  - Vascular Endothelial Growth Factor A/*metabolism/physiology
EDAT- 2011/01/22 06:00
MHDA- 2011/10/13 06:00
CRDT- 2011/01/22 06:00
PHST- 2011/01/22 06:00 [entrez]
PHST- 2011/01/22 06:00 [pubmed]
PHST- 2011/10/13 06:00 [medline]
AID - ajpgi.00047.2010 [pii]
AID - 10.1152/ajpgi.00047.2010 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2011 Aug;301(2):G210-9. doi: 
      10.1152/ajpgi.00047.2010. Epub 2011 Jan 20.