Mechanistic insights into isoform-dependent and species-specific regulation of bile salt export pump by farnesoid X receptor

Song, Xiulong; Chen, Yuan; Valanejad, Leila; Kaimal, Rajani; Yan, Bingfang; Stoner, Michael W.; Deng, Ruitang

doi:10.1194/jlr.m038323

Cited by 31 publications

(24 citation statements)

References 40 publications

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“…Regulation of BA metabolism is complicated and is affected by multiple factors. We decided to focus on the potential role of FXR in the present case not only because FXR regulates BA metabolism at multiple points, including the transcriptional expression of Bsep and several other genes whose promoters contain FXR response elements (FXRE), but also because FXR had been shown to interplay with autophagy function in a negative fashion under the fed condition . Autophagy function could in turn affect FXR, but this possibility had not been studied.…”

Section: Resultsmentioning

confidence: 99%

Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury

Khambu

Yan

et al. 2019

Hepatology

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Autophagy is important for hepatic homeostasis, nutrient regeneration, and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy because of the lack of autophagy-related gene 7 or autophagy-related gene 5, key autophagyrelated genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of tauromuricholic acid/taurocholic acid in the bile, increased hepatic bile acid load, abnormal bile canaliculi, and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and up-regulated expression of farnesoid X receptor (Fxr ) in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly bile salt export pump, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy-deficient livers. In addition, codeletion of nuclear factor erythroid 2-related factor 2 (Nrf2 ) in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy-deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion. Conclusion: Together with earlier reports that FXR can suppress autophagy, our findings indicate that autophagy and FXR form a regulatory loop and deficiency of autophagy causes abnormal FXR functionality, leading to the development of intracellular cholestasis and liver injury. (Hepatology 2019;69:2196-2213).

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Section: Resultsmentioning

confidence: 99%

Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury

Khambu

Yan

et al. 2019

Hepatology

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“…Chromatins were prepared from Huh 7 cells transfected with 2 μg ERα and FXR plasmids, followed by treatment of transfected cells with 10 μM CDCA and 100 nM E2 or 1% EtOH for 1 or 24 hours. ChIP assays were performed with the ChIP‐IT Express Kit (Active Motif) following the procedure described elsewhere …”

Section: Methodsmentioning

confidence: 99%

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

et al. 2014

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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.

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“…Each group of mice were hydrodynamically injected with mouse BSEP promoter reporter pmBSEP(Ϫ2.6kb) (0.5 g/g) and pcNDA5 vector, ER␣ wt, ER␣-AD, or ER␣-CF (0.5 g/g). Luciferase activities were detected by IVIS on days 1 and 7 after injection as previously described (25,26). The same groups of mice were then treated with E2 (5 mg/kg daily for 3 d sc), followed by detection of luciferase activities by IVIS on days 1 and 7 after treatment.…”

Section: Living Imaging With In Vivo Imaging System (Ivis)mentioning

confidence: 99%

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

Chen

Василенко

Song

et al. 2015

Molecular Endocrinology

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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.

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Mechanistic insights into isoform-dependent and species-specific regulation of bile salt export pump by farnesoid X receptor

Cited by 31 publications

References 40 publications

Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury

Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury

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

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

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