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.