L-tryptophan-mediated Enhancement of Susceptibility to Nonalcoholic Fatty Liver Disease is Dependent on the Mammalian Target of Rapamycin

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Aug 16

PMID 21841000

Citations 41

Authors

Yosuke Osawa

Hiromitsu Kanamori

Ekihiro Seki

Masato Hoshi

Hirofumi Ohtaki

Yoichi Yasuda

Hiroyasu Ito

Atsushi Suetsugu

Masahito Nagaki

Hisataka Moriwaki

Kuniaki Saito

Mitsuru Seishima

Affiliations

Soon will be listed here.

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.

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References

Lynch C, Halle B, Fujii H, Vary T, Wallin R, Damuni Z . Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR. Am J Physiol Endocrinol Metab. 2003; 285(4):E854-63. DOI: 10.1152/ajpendo.00153.2003. View

Toye A, Dumas M, Blancher C, Rothwell A, Fearnside J, Wilder S . Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice. Diabetologia. 2007; 50(9):1867-1879. DOI: 10.1007/s00125-007-0738-5. View

Angulo P . Nonalcoholic fatty liver disease. N Engl J Med. 2002; 346(16):1221-31. DOI: 10.1056/NEJMra011775. View

Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M . Autophagy regulates lipid metabolism. Nature. 2009; 458(7242):1131-5. PMC: 2676208. DOI: 10.1038/nature07976. View

Nocito A, Dahm F, Jochum W, Jang J, Georgiev P, Bader M . Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis. Gastroenterology. 2007; 133(2):608-18. DOI: 10.1053/j.gastro.2007.05.019. View

Forrest C, MacKay G, Stoy N, Egerton M, Christofides J, Stone T . Tryptophan loading induces oxidative stress. Free Radic Res. 2004; 38(11):1167-71. DOI: 10.1080/10715760400011437. View

Lim J, Mietus-Snyder M, Valente A, Schwarz J, Lustig R . The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010; 7(5):251-64. DOI: 10.1038/nrgastro.2010.41. View

Lesurtel M, Soll C, Graf R, Clavien P . Role of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives. Cell Mol Life Sci. 2007; 65(6):940-52. PMC: 11131662. DOI: 10.1007/s00018-007-7377-3. View

Facer P, Polak J, Jaffe B, Pearse A . Immunocytochemical demonstration of 5-hydroxytryptamine in gastrointestinal endocrine cells. Histochem J. 1979; 11(1):117-21. DOI: 10.1007/BF01041271. View

10.

Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, Webb M, Blendis L, Halpern Z . Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol. 2007; 47(5):711-7. DOI: 10.1016/j.jhep.2007.06.020. View

11.

Liu H, Han J, Cao S, Hong T, Zhuo D, Shi J . Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J Biol Chem. 2009; 284(45):31484-92. PMC: 2781544. DOI: 10.1074/jbc.M109.033936. View

12.

Osawa Y, Seki E, Kodama Y, Suetsugu A, Miura K, Adachi M . Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression. FASEB J. 2010; 25(4):1133-44. PMC: 3058702. DOI: 10.1096/fj.10-168351. View

13.

Dennis P, Fumagalli S, Thomas G . Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation. Curr Opin Genet Dev. 1999; 9(1):49-54. DOI: 10.1016/s0959-437x(99)80007-0. View

14.

Wilson F, Suryawan A, Orellana R, Gazzaneo M, Nguyen H, Davis T . Differential effects of long-term leucine infusion on tissue protein synthesis in neonatal pigs. Amino Acids. 2010; 40(1):157-65. PMC: 3139360. DOI: 10.1007/s00726-010-0629-9. View

15.

Lang P, Contaldo C, Georgiev P, El-Badry A, Recher M, Kurrer M . Aggravation of viral hepatitis by platelet-derived serotonin. Nat Med. 2008; 14(7):756-61. DOI: 10.1038/nm1780. View

16.

Lynch C, Hutson S, Patson B, Vaval A, Vary T . Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats. Am J Physiol Endocrinol Metab. 2002; 283(4):E824-35. DOI: 10.1152/ajpendo.00085.2002. View

17.

Stiles B, Wang Y, Stahl A, Bassilian S, Lee W, Kim Y . Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci U S A. 2004; 101(7):2082-7. PMC: 357055. DOI: 10.1073/pnas.0308617100. View

18.

Matthies D, Jacobs F . Rat liver is not damaged by high dose tryptophan treatment. J Nutr. 1993; 123(5):852-9. DOI: 10.1093/jn/123.5.852. View

19.

Hirata Y, Kawachi T, Sugimura T . Fatty liver induced by injection of L-tryptophan. Biochim Biophys Acta. 1967; 144(2):233-41. View

20.

Raught B, Gingras A, Sonenberg N . The target of rapamycin (TOR) proteins. Proc Natl Acad Sci U S A. 2001; 98(13):7037-44. PMC: 34619. DOI: 10.1073/pnas.121145898. View