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-dependent Tauro-DBD transport was impaired in T296I

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

13 BSEP/SPGP expression varies dramatically among human liv

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

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

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

17 ly B member 11/bile salt export pump (ABCB11/BSEP).

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

19 atic cholestasis mutants partially activated BSEP.

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

21 owing to ABCB11 missense mutations affecting BSEP canalicular targeting.

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

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

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

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

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

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

28 facilitates parallel screening for MDR3 and BSEP inhibitors.

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

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

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

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

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

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

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

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

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

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

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

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

41 t inducer of cholestasis, strongly decreased BSEP expression.

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

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

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

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

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

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

48 2 quantification or below 15.6% and 6.4% for BSEP/ABCG11, respectively.

49 l liver were retrieved and immunostained for BSEP.

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

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

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

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

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

55 in several cell lines [Huh7, HepaRG, HepaRG BSEP (-/-)] and primary human hepatocytes, we hypothesiz

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

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

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

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

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

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

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

63 positive transcriptional regulator of human BSEP expression.

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

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

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

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

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

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

70 ich provides an explanation for the improved BSEP activity.

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

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

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

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

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

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

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

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

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

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

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

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

83 uggulipid treatment in Fisher rats increased BSEP mRNA.

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

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

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

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

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

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

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

91 siently before exchanging with intracellular BSEP-YFP pools.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

109 Immunohistochemical evidence of BSEP deficiency correlates well with demonstrable mutati

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

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

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

113 Immunostaining of BSEP was performed in 20 patients.

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

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

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

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

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

119 be aggravated by simultaneous inhibition of BSEP and MDR3.

120 ity did not display a parallel inhibition of BSEP.

121 spholipid secretion as well as inhibition of BSEP.

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

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

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

125 t the canaliculus owing to mistrafficking of BSEP mutants.

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

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

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

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

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

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

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

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

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

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

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

137 Restoration of BSEP expression through suppressing inflammation in the

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

159 he downstream targets bile salt export pump (BSEP) and small heterodimer partner (SHP) in vitro, with

160 Bile salt export pump (BSEP) deficiency, or progressive familial intrahepatic c

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

162 aberrant radixin and bile salt export pump (BSEP) distribution, without an overt increase in TJ perm

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

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

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

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

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

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

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

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

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

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

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

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

175 11, which encodes the bile salt export pump (BSEP), a liver-specific adenosine triphosphate (ATP)-bin

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

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

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

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

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

181 ess inhibition of the bile salt export pump (BSEP), mitotoxicity, reactive metabolite (RM) formation,

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

183 eptide (NTCP) and the bile salt export pump (BSEP), respectively, in two-week cultures of HuH-7 cells

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

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

186 er partner (SHP), and bile salt export pump (BSEP).

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

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

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

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

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

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

193 oding the canalicular bile salt export pump (BSEP).

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

195 rs2302387 and ABCB11 [bile salt export pump (BSEP)] rs4668115 reduce transporter expression (P < 0.05

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

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

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

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

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

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

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

203 nt is responsible for the identified reduced BSEP expression.

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

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

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

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

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

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

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

211 of miR-210 inhibited MLL4 and, subsequently, BSEP and SHP expression, resulting in defective BA metab

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

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

214 Considering that BSEP activity directly depends on canalicular membrane c

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

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

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

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

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

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

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

222 demonstrated direct binding of MARE1 in the BSEP promoter.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

240 ffering from intrahepatic cholestasis due to BSEP deficiency.

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

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

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

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

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

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

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

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

249 fs were reached, 36/41 (87.8%) patients with BSEP deficiency were correctly classified as subsequent

250 BAs from 41 odevixibat-treated patients with BSEP deficiency who participated in PEDFIC were analyzed

251 uent response to odevixibat in patients with BSEP deficiency, to improve our understanding of the mec

252 uent response to odevixibat in patients with BSEP deficiency.

253 id (sBA) concentration in some patients with BSEP deficiency.

254 ile acid secretion capacity in patients with BSEP deficiency.