PMID- 21841000
OWN - NLM
STAT- MEDLINE
DCOM- 20111209
LR  - 20220309
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 286
IP  - 40
DP  - 2011 Oct 7
TI  - L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver 
      disease is dependent on the mammalian target of rapamycin.
PG  - 34800-8
LID - 10.1074/jbc.M111.235473 [doi]
AB  - Nonalcoholic fatty liver disease is one of the most common liver diseases. 
      L-tryptophan and its metabolite serotonin are involved in hepatic lipid 
      metabolism and inflammation. However, it is unclear whether L-tryptophan promotes 
      hepatic steatosis. To explore this issue, we examined the role of L-tryptophan in 
      mouse hepatic steatosis by using a high fat and high fructose diet (HFHFD) model. 
      L-tryptophan treatment in combination with an HFHFD exacerbated hepatic 
      steatosis, expression of HNE-modified proteins, hydroxyproline content, and serum 
      alanine aminotransaminase levels, whereas L-tryptophan alone did not result in 
      these effects. We also found that L-tryptophan treatment increases serum 
      serotonin levels. The introduction of adenoviral aromatic amino acid 
      decarboxylase, which stimulates the serotonin synthesis from L-tryptophan, 
      aggravated hepatic steatosis induced by the HFHFD. The fatty acid-induced 
      accumulation of lipid was further increased by serotonin treatment in cultured 
      hepatocytes. These results suggest that L-tryptophan increases the sensitivity to 
      hepatic steatosis through serotonin production. Furthermore, L-tryptophan 
      treatment, adenoviral AADC introduction, and serotonin treatment induced 
      phosphorylation of the mammalian target of rapamycin (mTOR), and a potent mTOR 
      inhibitor rapamycin attenuated hepatocyte lipid accumulation induced by fatty 
      acid with serotonin. These results suggest the importance of mTOR activation for 
      the exacerbation of hepatic steatosis. In conclusion, L-tryptophan exacerbates 
      hepatic steatosis induced by HFHFD through serotonin-mediated activation of mTOR.
FAU - Osawa, Yosuke
AU  - Osawa Y
AD  - Departments of Informative Clinical Medicine, Gifu University Graduate School of 
      Medicine, Gifu 501-1194, Japan. osawa-gif@umin.ac.jp
FAU - Kanamori, Hiromitsu
AU  - Kanamori H
FAU - Seki, Ekihiro
AU  - Seki E
FAU - Hoshi, Masato
AU  - Hoshi M
FAU - Ohtaki, Hirofumi
AU  - Ohtaki H
FAU - Yasuda, Yoichi
AU  - Yasuda Y
FAU - Ito, Hiroyasu
AU  - Ito H
FAU - Suetsugu, Atsushi
AU  - Suetsugu A
FAU - Nagaki, Masahito
AU  - Nagaki M
FAU - Moriwaki, Hisataka
AU  - Moriwaki H
FAU - Saito, Kuniaki
AU  - Saito K
FAU - Seishima, Mitsuru
AU  - Seishima M
LA  - eng
GR  - R01 AA020172/AA/NIAAA NIH HHS/United States
GR  - R01 DK085252/DK/NIDDK NIH HHS/United States
GR  - R01 DK085252-01A1/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110812
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Lipids)
RN  - 0 (Triglycerides)
RN  - 30237-26-4 (Fructose)
RN  - 333DO1RDJY (Serotonin)
RN  - 343-65-7 (Kynurenine)
RN  - 8DUH1N11BX (Tryptophan)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 4.1.1.28 (Aromatic-L-Amino-Acid Decarboxylases)
SB  - IM
MH  - Adenoviridae/metabolism
MH  - Animal Feed
MH  - Animals
MH  - Aromatic-L-Amino-Acid Decarboxylases/metabolism
MH  - Fatty Liver/pathology
MH  - Fibrosis
MH  - Fructose/metabolism
MH  - Genetic Predisposition to Disease
MH  - Hepatocytes/metabolism
MH  - Kynurenine/metabolism
MH  - Lipids/chemistry
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Serotonin/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Triglycerides/metabolism
MH  - Tryptophan/*metabolism
PMC - PMC3186417
EDAT- 2011/08/16 06:00
MHDA- 2011/12/14 06:00
PMCR- 2011/08/12
CRDT- 2011/08/16 06:00
PHST- 2011/08/16 06:00 [entrez]
PHST- 2011/08/16 06:00 [pubmed]
PHST- 2011/12/14 06:00 [medline]
PHST- 2011/08/12 00:00 [pmc-release]
AID - S0021-9258(20)73862-7 [pii]
AID - M111.235473 [pii]
AID - 10.1074/jbc.M111.235473 [doi]
PST - ppublish
SO  - J Biol Chem. 2011 Oct 7;286(40):34800-8. doi: 10.1074/jbc.M111.235473. Epub 2011 
      Aug 12.