Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump

Abstract

Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17β-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α and farnesoid X receptor (FXR) and transrepression of BSEP by E2/ERα is an etiological contributing factor to intrahepatic cholestasis of pregnancy. Currently the mechanistic insights into such transrepression are not fully understood. In this study, the dynamics of coregulator recruitment to BSEP promoter after FXR activation and E2 treatment were established with quantitative chromatin immunoprecipitation assays. Coactivator peroxisome proliferator-activated receptor-γ coactivator-1 was predominantly recruited to the BSEP promoter upon FXR activation, and its recruitment was decreased by E2 treatment. Meanwhile, recruitment of nuclear receptor corepressor was markedly increased upon E2 treatment. Functional evaluation of ERα and ERβ chimeras revealed that domains AC of ERα are the determinants for ERα-specific transrepression on BSEP. Further studies with various truncated ERα proteins identified the domains in ERα responsible for ligand-dependent and ligand-independent transrepression. Truncated ERα-AD exhibited potent ligand-independent transrepressive activity, whereas ERα-CF was fully capable of transrepressing BSEP ligand dependently in vitro in Huh 7 cells and in vivo in mice. Both ERα-AD and ERα-CF proteins were associated with FXR in the coimmunoprecipitation assays. In conclusion, E2 repressed BSEP expression through diminishing peroxisome proliferator-activated receptor-γ coactivator-1 recruitment with a concurrent increase in nuclear receptor corepressor recruitment to the BSEP promoter. Domains AD and CF in ERα mediated ligand-independent and ligand-dependent transrepression on BSEP, respectively, through interacting with FXR.

Effect of Liver Disease on Hepatic Transporter Expression and Function

“…84 In vivo studies revealed that the transcriptional dynamics of BSEP were inversely correlated with serum 17β-estradiol (E2) levels, implicating E2 levels in the repression of BSEP, which may increase susceptibility to ICP. 85,86 In the same study, repression of BSEP expression also was demonstrated in human primary hepatocytes. 85 The procholestatic effects of estrogens and progesterone may also alter Mrp2; E2 administration causes endocytic internalization, as well as decreased expression and function of Mrp2 in rodents.…”

Effect of inducible nitric oxide synthase and neuropeptide Y in plasma and placentas from intrahepatic cholestasis of pregnancy

“…ICP has been associated with higher frequency of fetal distress and even SIUD. Although ICP is characterized by high maternal serum bile acids and raised reproductive hormones, while the knowledge on the mechanistic basis of ICP is greatly limited. At present, the research on ICP pathogenesis involves genetic factors, internal secretion [ , environmental factors, immune factors, cell apoptosis, liprprotein and so on.…”

The Role of Steroid Hormones in the Development of Intrahepatic Cholestasis of Pregnancy

“…In subsequent studies these authors demonstrated that 17β-estradiol decreases the expression of Bsep through the lowering of the peroxisome proliferator-activated receptor-γ coactivator-1, with a simultaneous decrease in nuclear receptors of co-repressors of Bsep promotors. They also identified the domain of ER-α responsible for transrepression of Bsep through interaction with FXR (Chen et al 2015). Mapping these interactions between steroids and the metabolism of bile acids helps us better understand the pathophysiology of ICP.…”