Serotonin Regulates Lipogenesis and Endoplasmic Reticulum Stress in Alcoholic Liver Disease

• Published in: Diabetes & metabolism journal Vol. 49; no. 4; pp. 798 - 811
• Main Authors: Hwang, Inseon, Nam, Jung Eun, Choi, Wonsuk, Choi, Won Gun, Lee, Eunji, Kim, Hyeongseok, Moon, Young-Ah, Park, Jun Yong, Kim, Hail
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Diabetes Association 01.07.2025; 대한당뇨병학회
• Subjects: alcoholics; Animals; Disease Models, Animal; endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; fatty liver; Female; Humans; Lipogenesis - drug effects; Lipogenesis - physiology; Liver - metabolism; Liver - pathology; liver diseases; Liver Diseases, Alcoholic - blood; Liver Diseases, Alcoholic - genetics; Liver Diseases, Alcoholic - metabolism; Liver Diseases, Alcoholic - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Original; Receptor, Serotonin, 5-HT2A - genetics; Receptor, Serotonin, 5-HT2A - metabolism; Receptor, Serotonin, 5-HT2B - genetics; Receptor, Serotonin, 5-HT2B - metabolism; receptors, serotonin; serotonin; Serotonin - blood; Serotonin - metabolism; tryptophan hydroxylase; Tryptophan Hydroxylase - genetics; Tryptophan Hydroxylase - metabolism; 내과학; Tryptophan hydroxylase; Fatty liver; Liver diseases; Serotonin; Alcoholics; Receptors, serotonin; Endoplasmic reticulum stress
• ISSN: 2233-6079; 2233-6087; 2233-6087
• DOI: 10.4093/dmj.2024.0215

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.