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

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.
Authors	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
Journal	Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 4824 (Nov 16 2018) ISSN: 2041-1723 [Electronic] England
PMID	30446669 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Hypolipidemic Agents Receptor, Serotonin, 5-HT2A Serotonin Antagonists Succinates sarpogrelate Serotonin Tph1 protein, mouse Tryptophan Hydroxylase
Topics	Animals Diet, High-Fat (adverse effects) Disease Models, Animal Gene Expression Profiling Gene Expression Regulation Humans Hypolipidemic Agents (pharmacology) Insulin Resistance Intestinal Mucosa (metabolism, pathology) Lipid Metabolism Liver (metabolism, pathology) Male Mice Mice, Knockout Non-alcoholic Fatty Liver Disease (etiology, genetics, pathology, prevention & control) Receptor, Serotonin, 5-HT2A (deficiency, genetics) Serotonin (metabolism) Serotonin Antagonists (pharmacology) Signal Transduction Succinates (pharmacology) Tryptophan Hydroxylase (deficiency, genetics)

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