Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (SNS) 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 5HTR1A/1B receptor agonists inhibit biliary hyperplasia in BDL rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis in mice. AIM: to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. APPROACH/RESULTS: While in vivo studies were performed in bile duct ligated (BDL) rats and the 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, liver fibrosis as well as the mRNA expression of pro-inflammatory 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 the expression of fibrosis and inflammation genes compared to controls. CONCLUSION: Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C axis may represent a novel therapeutic approach for the management of cholangiopathies including PSC.
Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis
Fabris, Luca;
2019
Abstract
Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (SNS) 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 5HTR1A/1B receptor agonists inhibit biliary hyperplasia in BDL rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis in mice. AIM: to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. APPROACH/RESULTS: While in vivo studies were performed in bile duct ligated (BDL) rats and the 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, liver fibrosis as well as the mRNA expression of pro-inflammatory 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 the expression of fibrosis and inflammation genes compared to controls. CONCLUSION: Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C axis may represent a novel therapeutic approach for the management of cholangiopathies including PSC.
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
