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

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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

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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, 286(40), 34800-34808. https://doi.org/10.1074/jbc.M111.235473