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

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.