Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease
Background Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine neurotransmitter that has various functions in central and peripheral tissues. While 5-HT is known to regulate various biological processes in liver, direct role of 5-HT and its receptors, especially 5-HT receptor 2A (HTR2A) and HTR2B,...
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Korean Diabetes Association
2025-07-01
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| Series: | Diabetes & Metabolism Journal |
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| Online Access: | http://e-dmj.org/upload/pdf/dmj-2024-0215.pdf |
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| author | Inseon Hwang Jung Eun Nam Wonsuk Choi Won Gun Choi Eunji Lee Hyeongseok Kim Young-Ah Moon Jun Yong Park Hail Kim |
| author_facet | Inseon Hwang Jung Eun Nam Wonsuk Choi Won Gun Choi Eunji Lee Hyeongseok Kim Young-Ah Moon Jun Yong Park Hail Kim |
| author_sort | Inseon Hwang |
| collection | DOAJ |
| description | Background Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine neurotransmitter that has various functions in central and peripheral tissues. While 5-HT is known to regulate various biological processes in liver, direct role of 5-HT and its receptors, especially 5-HT receptor 2A (HTR2A) and HTR2B, in development and progression of alcoholic liver disease (ALD) in vivo is not well understood. Methods Blood 5-HT level was measured from both human ALD patients and ethanol (EtOH) diet-fed mouse models. Gut-specific tryptophan hydroxylase 1 (Tph1) knockout mice, liver-specific Htr2a knockout mice, and liver-specific Htr2b knockout mice were fed with EtOH diet. Then we evaluated liver damage, hepatic steatosis, endoplasmic reticulum (ER) stress, and inflammation. Results Blood 5-HT concentrations are increased in both humans and mice with ALD. Both gut-specific Tph1 knockout and liver-specific Htr2a knockout mice are resistant to steatosis by down-regulating lipogenic pathways in liver of chronic EtOH diet-fed mice. Moreover, genetic inhibition of both gut-derived serotonin (GDS) synthesis and hepatic HTR2A signaling prevents ER stress in liver of chronic EtOH diet-fed mice. Additionally, we found that ablation of HTR2A signaling protects against disease progression by attenuating liver injury and inflammation in chronic plus binge EtOH diet-fed mice. Also, inhibiting HTR2A signaling ameliorates alcohol-induced liver injury and ER stress in an acute EtOH diet-fed mice model. Conclusion GDS directly regulates lipogenesis and ER stress via signaling through hepatic HTR2A in the context of ALD. Inhibiting HTR2A signaling protects against alcohol-induced steatosis, liver injury and disease progression in various ALD mouse models and may also provide a novel therapeutic strategy for ALD. |
| format | Article |
| id | doaj-art-d39678d1df7a41928ddd6b019b96e475 |
| institution | OA Journals |
| issn | 2233-6079 2233-6087 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Korean Diabetes Association |
| record_format | Article |
| series | Diabetes & Metabolism Journal |
| spelling | doaj-art-d39678d1df7a41928ddd6b019b96e4752025-08-20T02:37:10ZengKorean Diabetes AssociationDiabetes & Metabolism Journal2233-60792233-60872025-07-0149479881110.4093/dmj.2024.02152917Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver DiseaseInseon Hwang0Jung Eun Nam1Wonsuk Choi2Won Gun Choi3Eunji Lee4Hyeongseok Kim5Young-Ah Moon6Jun Yong Park7Hail Kim8 Department of Biopharmacy, Daejeon Health University, Daejeon, Korea Graduate School of Medical Science and Engineering, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, Korea Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Korea Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Korea Department of Molecular Medicine, Inha University College of Medicine, Incheon, Korea Department of Internal Medicine, Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Graduate School of Medical Science and Engineering, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, KoreaBackground Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine neurotransmitter that has various functions in central and peripheral tissues. While 5-HT is known to regulate various biological processes in liver, direct role of 5-HT and its receptors, especially 5-HT receptor 2A (HTR2A) and HTR2B, in development and progression of alcoholic liver disease (ALD) in vivo is not well understood. Methods Blood 5-HT level was measured from both human ALD patients and ethanol (EtOH) diet-fed mouse models. Gut-specific tryptophan hydroxylase 1 (Tph1) knockout mice, liver-specific Htr2a knockout mice, and liver-specific Htr2b knockout mice were fed with EtOH diet. Then we evaluated liver damage, hepatic steatosis, endoplasmic reticulum (ER) stress, and inflammation. Results Blood 5-HT concentrations are increased in both humans and mice with ALD. Both gut-specific Tph1 knockout and liver-specific Htr2a knockout mice are resistant to steatosis by down-regulating lipogenic pathways in liver of chronic EtOH diet-fed mice. Moreover, genetic inhibition of both gut-derived serotonin (GDS) synthesis and hepatic HTR2A signaling prevents ER stress in liver of chronic EtOH diet-fed mice. Additionally, we found that ablation of HTR2A signaling protects against disease progression by attenuating liver injury and inflammation in chronic plus binge EtOH diet-fed mice. Also, inhibiting HTR2A signaling ameliorates alcohol-induced liver injury and ER stress in an acute EtOH diet-fed mice model. Conclusion GDS directly regulates lipogenesis and ER stress via signaling through hepatic HTR2A in the context of ALD. Inhibiting HTR2A signaling protects against alcohol-induced steatosis, liver injury and disease progression in various ALD mouse models and may also provide a novel therapeutic strategy for ALD.http://e-dmj.org/upload/pdf/dmj-2024-0215.pdfalcoholicsfatty liverendoplasmic reticulum stressliver diseasesreceptors, serotoninserotonintryptophan hydroxylase |
| spellingShingle | Inseon Hwang Jung Eun Nam Wonsuk Choi Won Gun Choi Eunji Lee Hyeongseok Kim Young-Ah Moon Jun Yong Park Hail Kim Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease Diabetes & Metabolism Journal alcoholics fatty liver endoplasmic reticulum stress liver diseases receptors, serotonin serotonin tryptophan hydroxylase |
| title | Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease |
| title_full | Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease |
| title_fullStr | Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease |
| title_full_unstemmed | Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease |
| title_short | Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease |
| title_sort | serotonin regulates lipogenesis and endoplasmic reticulum stress in alcoholic liver disease |
| topic | alcoholics fatty liver endoplasmic reticulum stress liver diseases receptors, serotonin serotonin tryptophan hydroxylase |
| url | http://e-dmj.org/upload/pdf/dmj-2024-0215.pdf |
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