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

Abstract

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.

Biliary damage and liver fibrosis are ameliorated in a novel mouse model lacking l-histidine decarboxylase/histamine signaling

“…All reagents were obtained from Sigma-Aldrich, Co. (St. Louis, MO) unless otherwise indicated. Reagents and media for cell culture were obtained from Invitrogen Corporation (Carlsbad, CA) 2 , 16 . Total RNA was isolated from total liver tissues and purified cholangiocytes by the TRI Reagent from Sigma Life Science and reverse transcribed with the Reaction Ready First Strand cDNA Synthesis kit (Qiagen, Valencia, CA) 2 , 16 .…”

Neuroendocrine Changes in Cholangiocarcinoma Growth

“…Dopamine/dopamine receptors Upregulated [91] Promote [91] Limited previous studies Serotonin/5-HT receptors Upregulated [97] Promote [97] Functions may differ between receptors [95][96][97] Histamine/histamine receptors Upregulated [103] Promote [103][104][105] inhibit [106,107] Functions differ between H 1 /H 2 and H 3 /H 4 receptors [103][104][105][106][107] In conclusion, CCA tumors have altered expression levels of neuroendocrine mediators and their receptors, and targeting these signaling pathways may be a promising approach to establish novel treatments for CCA. During cholangiopathies such as primary sclerosing cholangitis (PSC), expression levels of mediators and receptors are upregulated, which induces cholangiocyte proliferation and secretion leading to ductular reaction and liver fibrosis.…”

“…However, a recent study has demonstrated that cholangiocytes express other receptor subtypes, 5-HT 2A , 5-HT 2B , and 5-HT 2C , and agonists for these receptors exacerbated ductular reaction and liver fibrosis in BDL rats [96]. Antagonists of these receptors attenuated BDL-induced liver damage in vivo, indicating that activation of serotonin receptors affects liver conditions differently depending on the receptor [96]. Immunohistochemistry for 48 samples from CCA patients identified elevated expression levels of TPH1 and decreased levels of MAO-A in CCA tumors [97].…”

“…Cholangiocytes express serotonin receptors 5-HT 1A and 5-HT 1B during BDL, and administration of serotonin receptor agonists (8-OH-DPAT for 5-HT 1A and anpirtoline for 5-HT 1B ) decreased BDL-induced ductular reaction and cholangiocyte proliferation by inhibiting elevation of cAMP and PKA activity [95]. However, a recent study has demonstrated that cholangiocytes express other receptor subtypes, 5-HT 2A , 5-HT 2B , and 5-HT 2C , and agonists for these receptors exacerbated ductular reaction and liver fibrosis in BDL rats [96]. Antagonists of these receptors attenuated BDL-induced liver damage in vivo, indicating that activation of serotonin receptors affects liver conditions differently depending on the receptor [96].…”

Hepatic stellate cell reprogramming via exosome-mediated CRISPR/dCas9-VP64 delivery

“…Liver fibrosis is the pathological reaction of various chronic pathogenic factors acting on the liver and causing tissue injury and repair, and it is the necessary stage of the development of many liver diseases to cirrhosis (Forbes & Newsome, 2016 ; Kyritsi et al., 2020 ). Studies have shown that hepatic fibrosis is a reversible process (Deng et al., 2018 ; Zhang et al., 2020 ).…”