Transcriptional dynamics of bile salt export pump during pregnancy: Mechanisms and implications in intrahepatic cholestasis of pregnancy

Abstract

Bile salt export pump (BSEP) is responsible for biliary secretion of bile acids, a rate limiting step in the enterohepatic circulation of bile acids and transactivated by nuclear receptor farnesoid x receptor (FXR). Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent disorder among diseases unique to pregnancy and primarily occurs in the third trimester of pregnancy with a hallmark of elevated serum bile acids. Currently, the transcriptional regulation of BSEP during pregnancy and its underlying mechanisms and involvement in ICP are not fully understood. In this study, the dynamics of BSEP transcription in vivo in the same group of pregnant mice before, during and after gestation were established with in vivo imaging system (IVIS). BSEP transcription was markedly repressed in the later stages of pregnancy and immediately recovered after parturition, resembling the clinical course of ICP in human. The transcriptional dynamics of BSEP was inversely correlated with serum 17β-estradiol (E2) levels before, during and after gestation. Further studies showed that E2 repressed BSEP expression in human primary hepatocytes, Huh 7 cells and in vivo in mice. Such transrepression of BSEP by E2 in vitro and in vivo required estrogen receptor α (ERα). Mechanistic studies with chromatin immunoprecipitation (ChIP), protein co-immunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) assays demonstrated that ERα directly interacted with FXR in living cells and in vivo in mice. In conclusion, BSEP expression was repressed by E2 in the late stages of pregnancy through a non-classical E2/ERα transrepressive pathway, directly interacting with FXR. E2-mediated repression of BSEP expression represents an etiological contributing factor to ICP and therapies targeting the ERα/FXR interaction may be developed for prevention and treatment of ICP.

Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function

“…High levels of estrogens and progesterone have been proposed to be responsible for the trans-inhibition of BSEP in the later stage of pregnancy [48], but transcriptional repression of BSEP expression by 17β-estradiol and epiallopregnanolone sulfate has recently been demonstrated, providing an alternative model for the development of ICP [62].…”

Progesterone Metabolites as Farnesoid X Receptor Inhibitors

“…Future work is likely to establish whether women with ICP have abnormalities in sulfation, as has been proposed [24]. There are data from in vivo rodent studies [2,25] and in vitro experiments [1] to show that liganded estrogen receptor-α can inhibit FXR and BSEP. Therefore, it is possible that raised levels of estrogen and progesterone metabolites in pregnancy act together to influence FXR and BSEP function.…”

“…The role of the three dominant estrogens (estrone, estradiol and estriol) in human pregnancy is not entirely clear, but there are data indicating that they play a role in stimulation of myometrial growth and breast growth, and that they promote cervical softening and the expression of myometrial oxytocin receptors at term. They also stimulate hepatic synthesis of binding proteins and clotting factors, and can influence bile acid and lipid homeostasis pathways [1,2,3]. One principal role of progesterone in pregnancy is maintenance of uterine quiescence, and levels of the hormone drop prior to the initiation of labour.…”

Gestational Intrahepatic Cholestasis: Etiology, Maternal Outcome, Fetal Outcome and Management: Review

“…Bu ise hepatositlerin içindeki toksik safra asit birikimini önleyen primer mekanizmadır. 32 Nükleer reseptör olan FXR, NR1H4 geninde kodlanmaktadır. 33,34 Gebelikte östrojen metaboliti olan 17-beta-östradiol, FXR'yi etkileyen bir yolak kullanarak BSEP'nin ekspresyonunu baskılamakta-dır.…”

“…33,34 Gebelikte östrojen metaboliti olan 17-beta-östradiol, FXR'yi etkileyen bir yolak kullanarak BSEP'nin ekspresyonunu baskılamakta-dır. 32 Progesteron metaboliti, iki monosülfat olan allopregnanolon sülfat ve epiallopregnanolon sülfat hepatik safra asidi transportunu direkt olarak bozmaktadır. 34 GİK'da artmış miktarda sülfatlanmış progesteron metabolitleri, FXR etkisini azaltarak serum ve hepatositlerde safra asidi seviyelerinin artmasına neden olmaktadır.…”