色氨酸羟化酶 1/单胺氧化酶 A/5-羟色胺/5-羟色胺受体 2A/2B/2C 轴的调节在胆汁淤积时调节胆汁增殖和肝纤维化。
Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase-A/5-Hydroxytryptamine/5-Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis.
机构信息
Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX.
出版信息
Hepatology. 2020 Mar;71(3):990-1008. doi: 10.1002/hep.30880. Epub 2019 Oct 18.
BACKGROUND AND AIMS
Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO-A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5-hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile-duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models.
APPROACH AND RESULTS
While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout (Mdr2 ) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO-A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2 mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2 mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2 mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2 mice, respectively. 5HT levels increase in Mdr2 mice and in PSC human patients compared to their controls and decrease in serum of Mdr2 mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2 mice. In vitro, cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO-A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls.
CONCLUSIONS
Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.
背景与目的
血清素（5-HT）是一种在中枢神经系统（CNS）以及胃肠道肠嗜铬细胞中合成的神经内分泌激素。色氨酸羟化酶（TPH1）和单胺氧化酶（MAO-A）分别是 5-HT 合成和分解代谢的关键酶。先前的研究表明，5-羟色胺受体（5HTR）1A/1B 受体激动剂可抑制胆管结扎（BDL）大鼠的胆管增生，而 5HTR2B 受体拮抗剂可减轻小鼠的肝纤维化（LF）。我们的目的是评估 5HTR2A/2B/2C 激动剂/拮抗剂在胆汁淤积模型中的作用。
方法和结果
在体内研究中，我们在 BDL 大鼠和多药耐药基因 2 敲除（Mdr2）PSC 小鼠模型中进行了研究，在体外研究中，我们在胆管细胞和肝星状细胞（HSCs）的细胞系中进行了研究。5HTR2A/2B/2C 和 MAO-A/TPH1 在 BDL 大鼠和 Mdr2 小鼠的胆管细胞和 HSCs 中表达。在正常大鼠、BDL 大鼠和 Mdr2 小鼠中，5HTR2A/2B/2C 激动剂处理后，胆管反应、LF 以及促炎基因的 mRNA 表达增加，但与 BDL 大鼠和 Mdr2 小鼠相比，5HTR2A/2B/2C 拮抗剂处理后则减少。与对照相比，Mdr2 小鼠和 PSC 人类患者的 5-HT 水平升高，与未治疗的 Mdr2 小鼠相比，用 5HTR2A/2B/2C 拮抗剂治疗的 Mdr2 小鼠的血清中 5-HT 水平降低。在体外，鼠胆管细胞和人 HSCs 的细胞系表达 5HTR2A/2B/2C 和 MAO-A/TPH1；与对照组相比，用 5HTR2A/2B/2C 拮抗剂或 TPH1 抑制剂处理这些细胞系可降低 5-HT 水平以及纤维化和炎症基因的表达。
结论
调节 TPH1/MAO-A/5-HT/5HTR2A/2B/2C 轴可能是治疗包括 PSC 在内的胆管疾病的一种治疗方法。
Zotero 插件