Effect of maternal cholestasis on TGR5 expression in human and rat placenta at term

Abstract

Background & aims: TGR5 (Gpbar-1) is a plasma membrane-bound bile acid receptor expressed in several tissues, including liver, intestine and brain. High levels of TGR5 mRNA have been detected in human and rodent placenta, however, localization of the TGR5 protein has not been studied in this tissue. We aimed at characterizing TGR5 expression in placental tissue and investigated the effect of bile acids and progesterone metabolites, which accumulate during intrahepatic cholestasis of pregnancy (ICP), on receptor expression and localization.

Methods: TGR5 mRNA levels and cell-specific localization were determined by quantitative PCR and immunofluorescence, respectively.

Results: In human term placentas, TGR5 was mainly localized in fetal macrophages and to a lower extent in trophoblasts. In placentas from ICP patients and pregnant rats with obstructive cholestasis a marked down-regulation of TGR5 mRNA expression was observed. However, the cell-specific distribution of the TGR5 protein was unaffected. Besides bile acids, progesterone and its metabolites (5α-pregnan-3α-ol-20-one/5α-pregnan-3β-ol-20-one), which increase in serum during ICP, were able to dose-dependently activate TGR5. In addition, progesterone metabolites but not their sulfated derivatives nor taurolithocholic acid, significantly down-regulated TGR5 mRNA and protein expression in isolated human macrophages and a macrophage-derived cell line.

Conclusion: Since fetal macrophages and trophoblast cells are exposed to changes in the flux of compounds across the placental barrier, the expression of TGR5 in these cells together with its sensitivity to bile acids and progesterone metabolites regarding receptor activity and mRNA expression suggest that TGR5 may play a role in the effect of maternal cholestasis on the placenta.

Keywords: 5α-pregnan-3α-ol-20-one; 5α-pregnan-3β-ol-20-one; Bile acid; CK-7; Fetus; ICP; Liver; OCP; PBS; PM; PM-S; PM4; PM5; Pregnancy; Progesterone; Receptor; TLC; VeCad; alpha smooth muscle actin; cAMP; cyclic adenosine monophosphate; cytokeratin-7; intrahepatic cholestasis of pregnancy; obstructive cholestasis during pregnancy; phosphate buffered saline; progesterone metabolite; qPCR; real-time quantitative PCR; sulfated progesterone metabolite; taurolithocholic acid; vascular endothelial cadherine; αSMA.