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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 
 NATURE COMMUNICATIONS, Vol.9(1) : 4824, 2018 
Journal Title
Issue Date
Animals ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Hypolipidemic Agents/pharmacology ; Insulin Resistance ; Intestinal Mucosa/metabolism* ; Intestinal Mucosa/pathology ; Lipid Metabolism ; Liver/metabolism* ; Liver/pathology ; Male ; Mice ; Mice, Knockout ; Non-alcoholic Fatty Liver Disease/etiology ; Non-alcoholic Fatty Liver Disease/genetics* ; Non-alcoholic Fatty Liver Disease/pathology ; Non-alcoholic Fatty Liver Disease/prevention & control ; Receptor, Serotonin, 5-HT2A/deficiency ; Receptor, Serotonin, 5-HT2A/genetics* ; Serotonin/metabolism* ; Serotonin Antagonists/pharmacology ; Signal Transduction ; Succinates/pharmacology ; Tryptophan Hydroxylase/deficiency ; Tryptophan Hydroxylase/genetics*
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Lee, Hye Won(이혜원) ORCID logo https://orcid.org/0000-0002-3552-3560
Han, Kwang-Hyub(한광협) ORCID logo https://orcid.org/0000-0003-3960-6539
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