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 () and Hail Kim ()
Additional contact information
Wonsuk Choi: KAIST
Jun Namkung: KAIST
Inseon Hwang: KAIST
Hyeongseok Kim: KAIST
Ajin Lim: KAIST
Hye Jung Park: Severance Hospital
Hye Won Lee: Severance Hospital
Kwang-Hyub Han: Severance Hospital
Seongyeol Park: KAIST
Ji-Seon Jeong: Korea Research Institute of Standards and Science
Geul Bang: Korea Basic Science Institute
Young Hwan Kim: Korea Basic Science Institute
Vijay K. Yadav: Columbia University Medical Center
Gerard Karsenty: Columbia University Medical Center
Young Seok Ju: KAIST
Chan Choi: Chonnam National University Medical School
Jae Myoung Suh: KAIST
Jun Yong Park: Severance Hospital
Sangkyu Park: KAIST
Hail Kim: KAIST

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07287-7

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