Wonsuk Choi1, Jun Namkung1,2, Inseon Hwang3, Hyeongseok Kim1, Ajin Lim1, Hye Jung Park4, Hye Won Lee4, Kwang-Hyub Han4, Seongyeol Park1, Ji-Seon Jeong5, Geul Bang6, Young Hwan Kim6, Vijay K. Yadav7, Gerard Karsenty7, Young Seok Ju1, Chan Choi8, Jae Myoung Suh1,3, Jun Yong Park4,*, Sangkyu Park1,9,* & Hail Kim1,3,10,*
1Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea. 2Department of Biochemistry, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea. 3Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea. 4Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea. 5Center for Bioanalysis, Division of Metrology for Quality of Life, Korea Research Institute of Standards and Science, Daejeon 34113, Republic of Korea. 6Biomedical Omics Group, Korea Basic Science Institute, Chungbuk 28119, Republic of Korea. 7Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. 8Department of Pathology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea. 9Department of Biochemistry, College of Medicine, Catholic Kwandong University, Gangneung 25601, Republic of Korea. 10KAIST Institute for the BioCentury, KAIST, Daejeon 34141, Republic of Korea.
These authors contributed equally: Wonsuk Choi, Jun Namkung.
*Correspondence and requests for materials should be addressed to J.Y.P. or to S.P. or to H.K.
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.