L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin

Yosuke Osawa, Hiromitsu Kanamori, Ekihiro Seki, Masato Hoshi, Hirofumi Ohtaki, Yoichi Yasuda, Hiroyasu Ito, Atsushi Suetsugu, Masahito Nagaki, Hisataka Moriwaki, Kuniaki Saito, Mitsuru Seishima

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)34800-34808
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number40
DOIs
Publication statusPublished - 07-10-2011

Fingerprint

Sirolimus
Tryptophan
Liver
Serotonin
High Fat Diet
Nutrition
Fructose
Fats
Hepatocytes
Fatty Acids
Chemical activation
Non-alcoholic Fatty Liver Disease
Aromatic-L-Amino-Acid Decarboxylases
Lipids
Phosphorylation
Hydroxyproline
Metabolites
Serum
Lipid Metabolism
Alanine

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Osawa, Yosuke ; Kanamori, Hiromitsu ; Seki, Ekihiro ; Hoshi, Masato ; Ohtaki, Hirofumi ; Yasuda, Yoichi ; Ito, Hiroyasu ; Suetsugu, Atsushi ; Nagaki, Masahito ; Moriwaki, Hisataka ; Saito, Kuniaki ; Seishima, Mitsuru. / L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 40. pp. 34800-34808.
@article{f9b7cea53e544a5c80f7966e2b94bed3,
title = "L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin",
abstract = "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.",
author = "Yosuke Osawa and Hiromitsu Kanamori and Ekihiro Seki and Masato Hoshi and Hirofumi Ohtaki and Yoichi Yasuda and Hiroyasu Ito and Atsushi Suetsugu and Masahito Nagaki and Hisataka Moriwaki and Kuniaki Saito and Mitsuru Seishima",
year = "2011",
month = "10",
day = "7",
doi = "10.1074/jbc.M111.235473",
language = "English",
volume = "286",
pages = "34800--34808",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "40",

}

Osawa, Y, Kanamori, H, Seki, E, Hoshi, M, Ohtaki, H, Yasuda, Y, Ito, H, Suetsugu, A, Nagaki, M, Moriwaki, H, Saito, K & Seishima, M 2011, 'L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin', Journal of Biological Chemistry, vol. 286, no. 40, pp. 34800-34808. https://doi.org/10.1074/jbc.M111.235473

L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin. / Osawa, Yosuke; Kanamori, Hiromitsu; Seki, Ekihiro; Hoshi, Masato; Ohtaki, Hirofumi; Yasuda, Yoichi; Ito, Hiroyasu; Suetsugu, Atsushi; Nagaki, Masahito; Moriwaki, Hisataka; Saito, Kuniaki; Seishima, Mitsuru.

In: Journal of Biological Chemistry, Vol. 286, No. 40, 07.10.2011, p. 34800-34808.

Research output: Contribution to journalArticle

TY - JOUR

T1 - L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin

AU - Osawa, Yosuke

AU - Kanamori, Hiromitsu

AU - Seki, Ekihiro

AU - Hoshi, Masato

AU - Ohtaki, Hirofumi

AU - Yasuda, Yoichi

AU - Ito, Hiroyasu

AU - Suetsugu, Atsushi

AU - Nagaki, Masahito

AU - Moriwaki, Hisataka

AU - Saito, Kuniaki

AU - Seishima, Mitsuru

PY - 2011/10/7

Y1 - 2011/10/7

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=80053433530&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053433530&partnerID=8YFLogxK

U2 - 10.1074/jbc.M111.235473

DO - 10.1074/jbc.M111.235473

M3 - Article

VL - 286

SP - 34800

EP - 34808

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 40

ER -