Serotonin signals through a gut-liver axis to regulate hepatic steatosis

Wonsuk Choi, Jun Namkung, Inseon Hwang, Hyeongseok Kim, Ajin Lim, Hye Jung Park, Hye Won Lee, Kwang Hyub Han, Seongyeol Park, Ji Seon Jeong, Geul Bang, Young Hwan Kim, Vijay K. Yadav, Gerard Karsenty, Young Seok Ju, Chan Choi, Jae Myoung Suh, Jun Yong Park, Sangkyu Park, Hail Kim

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is increasing in worldwide prevalence, closely tracking the obesity epidemic, but specific pharmaceutical treatments for NAFLD are lacking. Defining the key molecular pathways underlying the pathogenesis of NAFLD is essential for developing new drugs. Here we demonstrate that inhibition of gut-derived serotonin synthesis ameliorates hepatic steatosis through a reduction in liver serotonin receptor 2A (HTR2A) signaling. Local serotonin concentrations in the portal blood, which can directly travel to and affect the liver, are selectively increased by high-fat diet (HFD) feeding in mice. Both gut-specific Tph1 knockout mice and liver-specific Htr2a knockout mice are resistant to HFD-induced hepatic steatosis, without affecting systemic energy homeostasis. Moreover, selective HTR2A antagonist treatment prevents HFD-induced hepatic steatosis. Thus, the gut TPH1-liver HTR2A axis shows promise as a drug target to ameliorate NAFLD with minimal systemic metabolic effects.

Original languageEnglish
Article number4824
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Choi, W., Namkung, J., Hwang, I., Kim, H., Lim, A., Park, H. J., Lee, H. W., Han, K. H., Park, S., Jeong, J. S., Bang, G., Kim, Y. H., Yadav, V. K., Karsenty, G., Ju, Y. S., Choi, C., Suh, J. M., Park, J. Y., Park, S., & Kim, H. (2018). Serotonin signals through a gut-liver axis to regulate hepatic steatosis. Nature communications, 9(1), [4824]. https://doi.org/10.1038/s41467-018-07287-7