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

• Published in: Nature communications Vol. 9; no. 1; pp. 4824 - 9
• Main Authors: Choi, Wonsuk, Namkung, Jun, Hwang, Inseon, Kim, Hyeongseok, Lim, Ajin, Park, Hye Jung, Lee, Hye Won, Han, Kwang-Hyub, Park, Seongyeol, Jeong, Ji-Seon, Bang, Geul, Kim, Young Hwan, Yadav, Vijay K., Karsenty, Gerard, Ju, Young Seok, Choi, Chan, Suh, Jae Myoung, Park, Jun Yong, Park, Sangkyu, Kim, Hail
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-11-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/63; 38; 38/77; 38/91; 631/443/319/1642; 64; 64/60; 692/4020/4021/1607/2750; Animals; Diet, High-Fat - adverse effects; Disease Models, Animal; Energy balance; Epidemics; Fatty liver; Gene Expression Profiling; Gene Expression Regulation; High fat diet; Homeostasis; Humanities and Social Sciences; Humans; Hypolipidemic Agents - pharmacology; Insulin Resistance; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Lipid Metabolism; Liver; Liver - metabolism; Liver - pathology; Liver diseases; Male; Mice; Mice, Knockout; multidisciplinary; 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; Pathogenesis; Receptor, Serotonin, 5-HT2A - deficiency; Receptor, Serotonin, 5-HT2A - genetics; Rodents; Science; Science (multidisciplinary); Serotonin; Serotonin - metabolism; Serotonin Antagonists - pharmacology; Signal Transduction; Steatosis; Succinates - pharmacology; Tryptophan Hydroxylase - deficiency; Tryptophan Hydroxylase - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07287-7

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.
No effective pharmacological treatments exist for nonalcoholic fatty liver disease (NAFLD). Here, the authors show that serotonin concentration in the portal blood is increased in nine human subjects and in mice fed a high-fat diet, and that local serotonin signaling ablation, either genetically or with an antagonist, prevents hepatic steatosis in mice.