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.
authors.affiliation: Departments of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. osawa-gif@umin.ac.jp
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Osawa
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.forename: Masato
authors.initials: M
authors.lastname: Hoshi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohtaki
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yasuda
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suetsugu
authors.forename: Masahito
authors.initials: M
authors.lastname: Nagaki
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D005234:Fatty Liver / Q000473:pathology; D005355:Fibrosis; D005632:Fructose / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012701:Serotonin / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D008055:Lipids; D014280:Triglycerides; D005632:Fructose; D012701:Serotonin; D007737:Kynurenine; D014364:Tryptophan; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D001142:Aromatic-L-Amino-Acid Decarboxylases