Hwang Inseon, Nam Jung Eun, Choi Wonsuk, Choi Won Gun, Lee Eunji, Kim Hyeongseok, Moon Young-Ah, Park Jun Yong, Kim Hail
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.
Diabetes Metab J. 2025 Jul;49(4):798-811. doi: 10.4093/dmj.2024.0215. Epub 2025 Feb 5.
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.
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.
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.
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.
血清素（5-羟色胺[5-HT]）是一种单胺神经递质，在中枢和外周组织中具有多种功能。虽然已知5-HT可调节肝脏中的各种生物学过程，但5-HT及其受体，尤其是5-HT受体2A（HTR2A）和HTR2B在体内酒精性肝病（ALD）发生发展中的直接作用尚不清楚。
检测人类ALD患者和乙醇（EtOH）饮食喂养小鼠模型的血液5-HT水平。给肠道特异性色氨酸羟化酶1（Tph1）敲除小鼠、肝脏特异性Htr2a敲除小鼠和肝脏特异性Htr2b敲除小鼠喂食EtOH饮食。然后我们评估肝脏损伤、肝脂肪变性、内质网（ER）应激和炎症。
ALD患者和小鼠的血液5-HT浓度均升高。肠道特异性Tph1敲除小鼠和肝脏特异性Htr2a敲除小鼠均通过下调慢性EtOH饮食喂养小鼠肝脏中的脂肪生成途径而对脂肪变性具有抗性。此外，肠道源性血清素（GDS）合成和肝脏HTR2A信号传导的基因抑制可预防慢性EtOH饮食喂养小鼠肝脏中的ER应激。此外，我们发现HTR2A信号传导的缺失通过减轻慢性加暴饮EtOH饮食喂养小鼠的肝脏损伤和炎症来预防疾病进展。此外，在急性EtOH饮食喂养小鼠模型中，抑制HTR2A信号传导可改善酒精性肝损伤和ER应激。
在ALD背景下，GDS通过肝脏HTR2A信号传导直接调节脂肪生成和ER应激。抑制HTR2A信号传导可预防各种ALD小鼠模型中的酒精性脂肪变性、肝损伤和疾病进展，也可能为ALD提供一种新的治疗策略。
