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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 an 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 17?-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 ? (ER?). Mechanistic studies with chromatin immunoprecipitation (ChIP), protein coimmunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC) assays demonstrated that ER? directly interacted with FXR in living cells and in vivo in mice.BSEP expression was repressed by E2 in the late stages of pregnancy through a nonclassical E2/ER? transrepressive pathway, directly interacting with FXR. E2-mediated repression of BSEP expression represents an etiological contributing factor to ICP and therapies targeting the ER?/FXR interaction may be developed for prevention and treatment of ICP.

SUBMITTER: Song X

PROVIDER: S-EPMC4194188 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Song Xiulong X Vasilenko Alexander A Chen Yuan Y Valanejad Leila L Verma Ruchi R Yan Bingfang B Deng Ruitang R

Hepatology (Baltimore, Md.) 20140519 6

<h4>Unlabelled</h4>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 d ...[more]

PMID: 24729004

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Project description:Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the ATP8B1 gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the ABCB11 gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). For surgeries performed prior to transplantation, BSEP patients were divided into two groups, BSEP-common (bearing common missense mutations D482G or E297G, with likely residual function) and BSEP-other. We evaluated clinical and biochemical outcomes in these patients. Overall, diversion improved biochemical parameters, pruritus, and growth, with substantial variation in individual response. BSEP-common or FIC1 patients survived longer after diversion without developing cirrhosis, being listed for or undergoing liver transplantation, or dying, compared to BSEP-other patients. Transplantation resolved cholestasis in all groups. However, FIC1 patients commonly developed hepatic steatosis, diarrhea, and/or pancreatic disease after transplant accompanied by biochemical abnormalities and often had continued poor growth. In BSEP patients with impaired growth, this generally improved after transplantation. Conclusion: Diversion can improve clinical and biochemical status in FIC1 and BSEP deficiencies, but outcomes differ depending on genetic etiology. For many patients, particularly BSEP-other, diversion is not a permanent solution and transplantation is required. Although transplantation resolves cholestasis in patients with FIC1 and BSEP deficiencies, the overall outcome remains unsatisfactory in many FIC1 patients; this is mainly due to extrahepatic manifestations. (Hepatology Communications 2018;2:515-528).

Project description:BackgroundICP pregnant women have a unique profile of serum bile acid metabolism, thus the early and accurate identification of ICP patients is beneficial to early appropriate treatment and improvement of pregnancy outcomes. In this study, ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS) was used to analyze the 15 types of serum bile acid profiles among patients with ICP in third trimester, patients with cholelithiasis, and patients with hepatitis B virus. The ICP diagnostic model established by partial least squares-discriminant analysis (PLS-DA) was used to screen the differential bile acids for clinical subtypes of ICP. 144 cases of ICP patients were involved in this study, and divided into four subgroups according to serum level of TBA, DBIL, and ALT.Results(1) The differential serum bile acid profiles of ICP group and normal pregnant women were DCA, TDCA, TCA, GDCA and GLCA. (2) The differential serum bile acid profiles of the ICP1 group (ICP with jaundice) and normal pregnant women were TCDCA, TCA, GCA, GCDCA, TUDCA and GUDCA. (3) The differential serum bile acid profiles of the ICP3 group (Hyperchoicemia of pregnancy) and normal pregnant group was GUDCA, LCA, GLCA, UDCA, TUDCA, CDCA, and TLCA (P < 0.05). (4) The differential serum bile acid profiles of ICP4 group (idiopathic aminotransferase abnormality during pregnancy) and normal pregnant group was UDCA, GUDCA, TUDCA, GCA and GLCA (P < 0.05). (5) The occurrence of meconium-stained amniotic fluid, premature delivery and cesarean section in ICP1 group was significantly higher than normal group, ICP2 group, ICP3 group, and ICP4 group (P < 0.05); The occurrence of meconium-stained amniotic fluid, premature delivery and cesarean section in ICP2 group, ICP3 group, and ICP4 group was significantly higher than normal group (P < 0.05), but no difference was found among ICP2 group, ICP3 group, and ICP4 group (P > 0.05).ConclusionMaternal serum bile acid profiles are useful to differentiate the four subtypes of ICP. ICP with jaundice could be an important predictor of adverse pregnancy outcomes of ICP.

Dataset Information

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

Publications

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

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