ライフサイエンスコーパス: BSEP

1 BSEP and HAX-1 were over-represented in rat liver subcel

2 BSEP and MLC2 were overrepresented in a rat liver subcel

3 BSEP deficiency leads to severe cholestasis and hepatoce

4 BSEP expression is severely diminished in HCC patients a

5 BSEP expression was repressed by E2 in the late stages o

6 BSEP is a target for inhibition and down-regulation by d

7 BSEP transcription was markedly repressed in the later s

8 BSEP, a member of the family of structurally related ade

9 BSEP, MDR1, and MDR2 ATP binding cassette transporters a

10 BSEP, MDR1, MDR2, and MRP2 ABC transporters are targeted

11 BSEP/Bsep gene expression is regulated by the nuclear fa

12 BSEP/SPGP expression varies dramatically among human liv

13 ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs. >24 months postope

14 Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation.

15 No mutation in ABCB11/BSEP or ATP8B1/FIC1 genes were identified.

16 Byler disease FIC1 mutants did not activate BSEP, whereas benign recurrent intrahepatic cholestasis

17 atic cholestasis mutants partially activated BSEP.

18 ndicated that HAX-1 depletion did not affect BSEP translation, post-translational modification, deliv

19 owing to ABCB11 missense mutations affecting BSEP canalicular targeting.

20 to be 31.25 pM and 125 nM for BCRP/ABCG2 and BSEP/ABCG11, respectively.

21 tion quantification method for BCRP/Bcrp and BSEP/Bsep and the differences of the protein expressions

22 The absolute differences of BCRP/Bcrp and BSEP/Bsep proteins were determined in livers and isolate

23 hat impair both mitochondrial energetics and BSEP functional activity are more sensitive to more seve

24 ALGS, FIC1, and BSEP patients experienced less severely scored pruritus

25 Pathological liver injuries improved, and BSEP, which was not detected at the canalicular membrane

26 facilitates parallel screening for MDR3 and BSEP inhibitors.

27 n mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific facto

28 drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe

29 MRP2 and BSEP were expressed with baculoviruses in insect cells,

30 toplasmic distribution of MYO5B, RAB11A, and BSEP in hepatocytes.

31 came activated as shown by increased SHP and BSEP mRNA levels and decreased CYP7A1 mRNA level and act

32 ased expression of its target genes, SHP and BSEP, and decreased CYP7A1 mRNA level and activity.

33 role in bile acid transport in placenta, as BSEP does in liver.

34 A similar correlation between BSEP and FXR isoform expression was confirmed in hepatom

35 Canalicular BSEP, mostly present in raft (high cholesterol) microdom

36 fied by mutations in a positional candidate, BSEP, which encodes a liver-specific ATP-binding cassett

37 Transport of the two most common BSEP variants p.444V/A showed Michaelis-Menten kinetics

38 ular membrane cholesterol content, decreased BSEP presence in rafts may contribute to BSEP activity d

39 t inducer of cholestasis, strongly decreased BSEP expression.

40 The decreased BSEP expression in HCC was associated with altered relat

41 t was also readily observed in FXR-dependent BSEP promoter activation using a luciferase reporter con

42 se letters identify the human protein, i.e., BSEP and BCRP, and lowercase letters indicate that the t

43 pump (BSEP) and mutation in ABCB11, encoding BSEP, underlay progressive familial intrahepatic cholest

44 oxycholate or GW4064, GS enhanced endogenous BSEP expression with a maximum induction of 400-500% tha

45 Induction of endogenous BSEP mRNA and Arg-17 methylation by FXR regulatory eleme

46 2 quantification or below 15.6% and 6.4% for BSEP/ABCG11, respectively.

47 l liver were retrieved and immunostained for BSEP.

48 light chain, MLC2, as a binding partner for BSEP, MDR1, and MDR2.

49 en identified HAX-1 as a binding partner for BSEP, MDR1, and MDR2.

50 as early as 3 h, and the ligand potency for BSEP regulation correlates with the intrinsic activity o

51 ings indicate that myosin II is required for BSEP trafficking to the apical membrane.

52 A minority had BSEP levels similar to wild-type.

53 However, BSEP expression, though reduced, is retained in the live

54 Human BSEP promoter activity was stimulated by Nrf2 in a dose-

55 criptional activation of the mouse and human BSEP/SPGP promoters.

56 assessed whether Nrf2 plays a role in human BSEP expression and if this might be mediated by MAREs.

57 o acids in TacCterm and in full-length human BSEP blocks the internalization.

58 In contrast to mice, human BSEP was regulated by farnesoid X receptor (FXR) in an i

59 CDCA induced endogenous expression of human BSEP by 10-12-fold and murine BSEP by 2-3-fold in primar

60 positive transcriptional regulator of human BSEP expression.

61 Computer software analysis of human BSEP reveals two musculo-aponeurotic fibrosacroma (Maf)

62 salt export protein, and mutations of human BSEP were identified as the cause of PFIC 2.

63 the ligand-dependent activation of the human BSEP locus is associated with a simultaneous increase of

64 scription through the IR-1 site in the human BSEP promoter.

65 ity than FXR-alpha1 in transactivating human BSEP in vitro and in vivo.

66 AdhAQP1 treatment was unable to improve BSEP protein expression in cholestasis; however, its tra

67 ich provides an explanation for the improved BSEP activity.

68 rocessing of BSEP protein, or alterations in BSEP protein function.

69 o, concurrent with a significant decrease in BSEP expression.

70 at might circumvent the profound decrease in BSEP/SPGP.

71 Intracellular carriers enriched in BSEP-YFP elongated and dissociated as tubular elements f

72 an understanding of the domain interplay in BSEP as a basis for exploration of drug interactions wit

73 Mutations in BSEP result in progressive intrahepatic cholestasis, a s

74 gest that HAX-1 and cortactin participate in BSEP internalization from the apical membrane.

75 indicate that FXR plays an important role in BSEP gene expression and that FXR ligands may be potenti

76 RNA interference of HAX-1 increased BSEP levels in the apical membrane of MDCK cells by 71%.

77 Consistently, CDCA increased BSEP mRNA by 750-fold in HepG2 cells, whereas DCA, CA, a

78 etic FXR ligand GW4064 effectively increased BSEP mRNA in both cell types.

79 ipraz, a potent activator of Nrf2, increased BSEP messenger RNA expression by approximately seven-fol

80 uggulipid treatment in Fisher rats increased BSEP mRNA.

81 In addition, GS alone slightly increased BSEP promoter activation in the absence of an FXR agonis

82 with these findings, CARM1 led to increased BSEP promoter activity with an intact FXR regulatory ele

83 (FXR/BAR) paralleled their ability to induce BSEP in human hepatocyte cultures.

84 pG2 cells, whereas DCA, CA, and UDCA induced BSEP mRNA by 250-, 75-, and 15-fold, respectively.

85 Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated

86 Intracellular BSEP at baseline was seen in six, of whom five were resp

87 t presentation, lower ALT, and intracellular BSEP expression are likely to respond, at least transien

88 siently before exchanging with intracellular BSEP-YFP pools.

89 To address this issue, BSEP endocytosis was studied by immunofluorescence and a

90 In the latter two locations, BSEP-YFP colocalized with rab11, an endosomal marker.

91 eak of metabolically labeled apical membrane BSEP at 4 h and enhanced retention at 6 and 9 h.

92 nging membrane cholesterol content modulates BSEP and MRP2 transport kinetics differently.

93 fer promotes biliary BS output by modulating BSEP activity in estrogen-induced cholestasis, a novel f

94 ssion of human BSEP by 10-12-fold and murine BSEP by 2-3-fold in primary hepatocytes.

95 t of the ability of 4-PB to retarget mutated BSEP.

96 some PFIC2 patients with missense mutations, BSEP is not detected at the canaliculus owing to mistraf

97 ent but did not reach the capacity of normal BSEP.

98 nce, understanding the functional biology of BSEP is of key importance.

99 ohistochemistry showed a gradual decrease of BSEP from zone 1 to zone 3 of the liver lobule, suggesti

100 tations are known to lead to a deficiency of BSEP in human hepatocytes, suggesting that PFIC II mutan

101 In humans, deficiency of BSEP, which is encoded by the ABCB11 gene, causes severe

102 In this study the dynamics of BSEP transcription in vivo in the same group of pregnant

103 The transcriptional dynamics of BSEP was inversely correlated with serum 17beta-estradio

104 one H3 within the FXR DNA-binding element of BSEP.

105 sed endocytic motif at the C-terminal end of BSEP.

106 Immunohistochemical evidence of BSEP deficiency correlates well with demonstrable mutati

107 ailable) had immunohistochemical evidence of BSEP deficiency; the eleventh child did not.

108 novo or retargeted canalicular expression of BSEP occurred in four of these six, two of whom exhibite

109 novo or retargeted canalicular expression of BSEP occurs in treatment responders; children with late-

110 Immunostaining of BSEP was performed in 20 patients.

111 One reason for functional impairment of BSEP is systemic administration of drugs, which as a sid

112 m their hierarchy and potency as inducers of BSEP in human hepatocytes.

113 XR agonist LG100268 antagonizes induction of BSEP expression mediated by endogenous and synthetic FXR

114 Induction of BSEP gene expression is mediated by the farnesoid X rece

115 Despite the partial induction of BSEP mRNA, CA, DCA, and UDCA effectively repressed expre

116 be aggravated by simultaneous inhibition of BSEP and MDR3.

117 ity did not display a parallel inhibition of BSEP.

118 spholipid secretion as well as inhibition of BSEP.

119 ndicate that constitutive internalization of BSEP is clathrin-mediated and dependent on the tyrosine-

120 e cortactin increased steady state levels of BSEP 2-fold in the apical membrane of MDCK cells, as did

121 hepatocytes conserved the protein levels of BSEP/Bsep and BCRP/Bcrp similarly to those found in live

122 t the canaliculus owing to mistrafficking of BSEP mutants.

123 thin could serve to regulate apical pools of BSEP as well as other apical membrane transporters.

124 lestasis through a delocalization process of BSEP at the lobular level.

125 ssenger RNA splicing, abnormal processing of BSEP protein, or alterations in BSEP protein function.

126 Cholesterol increases the transport rates of BSEP and MRP2, but with the latter, may also modify the

127 the mechanisms underlying the regulation of BSEP by bile acids, the promoter of the BSEP gene was cl

128 pG2 cells and prevented the up-regulation of BSEP by oltipraz.

129 Currently, the transcriptional regulation of BSEP during pregnancy and its underlying mechanisms and

130 we quantitatively analyzed the regulation of BSEP expression by FXR ligands in primary human hepatocy

131 imals may result from its down-regulation of BSEP through FXR.

132 of bile acids, due to the down-regulation of BSEP/SPGP-mediated efflux in FXR nullizygous mice, resul

133 E2-mediated repression of BSEP expression represents an etiological contributing f

134 Restoration of BSEP expression through suppressing inflammation in the

135 ferred to as Tac) and the C-terminal tail of BSEP (TacCterm).

136 way in hepatocytes, (2) altered targeting of BSEP to the canalicular membrane, and (3) increased ilea

137 otif in the carboxyl cytoplasmic terminus of BSEP was identified.

138 we studied the intracellular trafficking of BSEP tagged with yellow fluorescent protein (YFP) in pol

139 The regulation of trafficking of BSEP to and from the cell surface is not well understood

140 expression augmented the transactivation of BSEP and SHP promoters by FXR.

141 ted the ligand-dependent, transactivation of BSEP and SHP promoters by FXR/retinoid X receptor alpha

142 Such transrepression of BSEP by E2 in vitro and in vivo required estrogen recept

143 ability to enhance the action of agonists on BSEP expression in vivo.

144 binding domains and determined the effect on BSEP basal and substrate-stimulated ATPase activity as w

145 and nuclear localization and its effects on BSEP promoter activity could be blocked with protein kin

146 respectively; P = 0.02), but not in ALGS or BSEP.

147 vs. 24 months; P = 0.03), but not in FIC1 or BSEP.

148 icant changes in either biliary BS output or BSEP activity.

149 In contrast, SHP reporter or BSEP reporter genes were activated to similar degrees by

150 ated induction of small heterodimer partner, BSEP, and multidrug-resistant protein (MDR) 3/Mdr2.

151 (+)-taurocholate cotransporting polypeptide, BSEP, MDR3, and ABCG5/G8 and grown in the Transwell syst

152 PFIC patients with bile salt export protein (BSEP) genotype.

153 The bile salt excretory pump (BSEP, ABCb11) is critical for ATP-dependent transport of

154 ar bile transporters, bile salt export pump (BSEP) and multidrug resistance protein 3 (MDR3).

155 bile acid transporter bile salt export pump (BSEP) and mutation in ABCB11, encoding BSEP, underlay pr

156 sis-1 (FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low gamma-glutamyl tran

157 nd how they relate to bile salt export pump (BSEP) expression and its (re)targeting.

158 Bile salt export pump (BSEP) is a major bile acid transporter in the liver.

159 The bile salt export pump (BSEP) is an ATP-binding cassette transporter that serves

160 The liver-specific bile salt export pump (BSEP) is crucial for bile acid-dependent bile flow at th

161 Bile salt export pump (BSEP) is responsible for biliary secretion of bile acids

162 The bile salt export pump (BSEP) is the major determinant of bile salt-dependent bi

163 the inhibition of the bile salt export pump (BSEP) is well investigated, only limited information on

164 le acid effluxer, the bile salt export pump (BSEP) plays a vital role in maintaining bile acid homeos

165 The bile salt export pump (BSEP) plays an integral role in lipid homeostasis by reg

166 nstructs with a human bile salt export pump (BSEP) promoter and a variety of cellular localization te

167 ivation assays with a bile salt export pump (BSEP) promoter-driven luciferase construct, bile acids s

168 otein 2 (MRP2) and of bile salt export pump (BSEP) variants and mutants.

169 11, which encodes the bile salt export pump (BSEP), a liver-specific adenosine triphosphate (ATP)-bin

170 uced transcription of bile salt export pump (BSEP), a major hepatic bile acid transporter.

171 in the gene locus for bile salt export pump (BSEP), a well established FXR target gene that functions

172 ne encoding the human bile salt export pump (BSEP), ABCB11, is mutated in several forms of intrahepat

173 odimer partner (SHP), bile salt export pump (BSEP), and increased Cyp7A1.

174 mation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction.

175 esterol transporters (bile salt export pump (BSEP), Na(+)/taurocholate cotransporting polypeptide (NT

176 ns in ABCB11 encoding bile salt export pump (BSEP), the canalicular bile salt export pump of hepatocy

177 was recruited to the bile salt export pump (BSEP), the small heterodimer partner (SHP), and the OSTa

178 mer partner (SHP) and bile salt export pump (BSEP).

179 more dependent on the bile salt export pump (BSEP).

180 B11 gene encoding the bile salt export pump (BSEP).

181 is the major hepatic bile salt export pump (BSEP).

182 hat SPGP is the human bile salt export pump (BSEP).

183 ch do not express the bile salt export pump (BSEP).

184 porter alpha/beta and bile salt export pump (BSEP)] promoter reporter activity in a ligand-dependent

185 The bile salt export pump (BSEP, ABCB11) couples ATP hydrolysis with transport of b

186 The bile salt export pump (BSEP/ABCB11) transports bile salts from hepatocytes into

187 tein (BCRP/ABCG2) and bile salt export pump (BSEP/ABCG11) quantification, using insect membrane vesic

188 xpression of the canalicular BS export pump (BSEP; ABCB11).

189 embrane transporters (bile salt export pump [BSEP], multidrug resistance-associated protein [MRP] 2)

190 In AdhAQP1-transduced cholestatic rats, BSEP showed a canalicular microdomain distribution simil

191 zygous mice, which have dramatically reduced BSEP/SPGP levels, hepatic CYP3A11 and CYP2B10 were stron

192 similarly, after 24 hours it down-regulated BSEP and MDR3 in parallel to a decrease of NTCP and CYP8

193 contrast, low BA concentrations up-regulated BSEP and MDR3 in the absence of oxidative stress.

194 Further studies showed that E2 repressed BSEP expression in human primary hepatocytes, Huh 7 cell

195 Since BSEP is an energy-dependent protein responsible for the

196 tobleaching experiments revealed that single BSEP-YFP molecules resided in canalicular membranes only

197 f-p-glycoprotein/bile salt export pump (spgp/BSEP) was demonstrated to encode for the rat ATP-depende

198 horylatable MLC2 mutant reduced steady state BSEP levels in the apical domain of polarized Madin-Darb

199 These results suggest BSEP as a direct target of FXR and support the recent re

200 erely impaired delivery of newly synthesized BSEP to the apical surface.

201 Considering that BSEP activity directly depends on canalicular membrane c

202 We demonstrate that BSEP expression is dramatically regulated by ligands of

203 In this study, we found that BSEP expression was severely diminished in HCC tissues a

204 canalicular and intracellular membranes that BSEP constitutively cycles within could serve to regulat

205 Confocal imaging revealed that BSEP-YFP was localized at the canalicular membrane and i

206 ds showed distinct abilities to activate the BSEP promoter: CDCA, DCA, CA, and UDCA increased lucifer

207 n model cell lines, genetic mutations in the BSEP gene impair its targeting and transport function, c

208 bound to MARE1, but not MARE2 regions in the BSEP promoter in HepG2 cells.

209 demonstrated direct binding of MARE1 in the BSEP promoter.

210 mutation of the FXR response element in the BSEP promoter.

211 lpha heterodimers to the IR-1 element in the BSEP promoter.

212 n of BSEP by bile acids, the promoter of the BSEP gene was cloned.

213 ponse element (FXRE) located upstream of the BSEP gene.

214 ossibly at the level of transcription of the BSEP gene.

215 The increased occupation of the BSEP locus by CARM1 also corresponds with the increased

216 CARM1 necessary for full potentiation of the BSEP locus in vivo.

217 The transport activity of the BSEP mutants p.E297G and p.R432T increased at high chole

218 quired to attain full transactivation of the BSEP promoter by bile acids.

219 ociated with FXR-dependent activation of the BSEP promoter.

220 f FXR and support the recent report that the BSEP promoter is transactivated by FXR.

221 sed binding and/or recruitment of FXR to the BSEP and SHP promoters on ChIP-ReChIP.

222 e concurrent binding of FXR and Sumo1 to the BSEP and SHP promoters.

223 se in binding of FXR/RXR heterodimers to the BSEP-FXRE coupled with the inability of RXR agonists to

224 t, whereas CARM1 failed to transactivate the BSEP promoter with a mutated FXRE.

225 HAX-1 was bound to BSEP, MDR1, and MDR2 in canalicular membrane vesicles an

226 sed BSEP presence in rafts may contribute to BSEP activity decline in 17alpha-ethinylestradiol choles

227 ffering from intrahepatic cholestasis due to BSEP deficiency.

228 level (or both) contribute significantly to BSEP deficiency.

229 P-inhibition of Cyp7A1 and higher transport (BSEP) and detoxification (Sult2a1) leading to an improve

230 BT and decreased liver IL-10, FXR, CAR, VDR, BSEP, MRP2, MRP3, MRP4 was also observed in ANIT-induced

231 In conclusion, PFIC associated with BSEP deficiency represents a previously unrecognized ris

232 With respect to the other 3 children with BSEP deficiency, mutations in ABCB11 were demonstrated i

233 membrane vesicles, and MLC2 colocalized with BSEP in the apical domain of hepatocytes and polarized W

234 ular membrane vesicles and co-localized with BSEP and MDR1 in the apical membrane of Madin-Darby cani

235 BCB11 were demonstrated in all patients with BSEP deficiency in whom leukocyte DNA could be studied (