ライフサイエンスコーパス: ASBT

1 ASBT function is rapidly regulated by several posttransl

2 ASBT reclaims bile acids from the distal ileum via activ

3 ASBT regulation was studied in IL-1beta-treated IEC-6 an

4 ASBT(NM) contains two inverted structural repeats of fiv

5 rcinoma/Poliomyelitis Research Foundation/5- ASBT cells.

6 ing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility an

7 In addition, ASBT expression in farnesoid X receptor null mice was un

8 However, whether S-acylation affects ASBT function and membrane expression has not been deter

9 tives for their transport inhibition against ASBT, NTCP, and SOAT.

10 The crystal structure of an ASBT homologue from Neisseria meningitidis (ASBT(NM)) in

11 e acids, here we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBTYf) in a

12 lowered by specific inhibitors of ASBT, and ASBT is thus a target for hypercholesterolaemia drugs.

13 -based transport assays to evaluate NTCP and ASBT inhibitors.

14 t bile acid transporter, designated Ntcp and ASBT, respectively, revealed a 206-bp product in NRC who

15 n of the BA transporters FABP6, OSTbeta, and ASBT and decreased concentrations of secondary BA deoxyc

16 cluding the transporters NaDC3 (SLC13A3) and ASBT (SLC10A2).

17 of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestas

18 ave exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to th

19 cid transporter (ASBT), effectively blocking ASBT's function in the small intestine, maintaining the

20 ecially the mechanism of bile acid uptake by ASBT, and the development of bile acid-based oral drug d

21 The intestinal bile acid carrier ASBT (SLC10A2), the hepatic bile acid carrier NTCP (SLC1

22 In Caco-2 cells, ASBT messenger RNA expression was reduced 65% after inte

23 Bile acid transport by cholangiocyte ASBT can contribute to hepatobiliary secretion in vivo.

24 Here, we studied the mechanisms controlling ASBT protein levels in cholangiocytes to determine wheth

25 ical (ileal) sodium/bile acid cotransporter (ASBT) may be a promising new therapy for lowering of pla

26 iliary epithelia (ASBT-OVA mice) and crossed ASBT-OVA mice with mice that express ovalbumin in entero

27 ng that unsaturated fatty acids may decrease ASBT's function via a direct covalent interaction with A

28 crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.

29 c-Jun overexpression enhances ASBT promoter activity, whereas a dominant negative c-ju

30 isolated cholangiocytes if secretin enhances ASBT translocation to the apical membrane from latent pr

31 that express ovalbumin in biliary epithelia (ASBT-OVA mice) and crossed ASBT-OVA mice with mice that

32 nt of bile acid-based oral drug delivery for ASBT-targeting, including bile acid-based prodrugs, bile

33 normal rat liver showed that the message for ASBT was present only in cholangiocytes.

34 hese results have implications, not only for ASBT(NM) but for the BASS family as a whole and indeed o

35 ransporters, MABA uptake was efficient (NTCP>ASBT>OATP1B3) and inhibitable by TCA.

36 holate (TC) biliary transit time during high ASBT activity.

37 Human ASBT promoter activity was enhanced by c-jun and repress

38 Endogenously expressed human ASBT mRNA half-lives and steady-state protein levels in

39 nger RNA levels and a 78% reduction in human ASBT promoter activity.

40 an NTCP, mouse mNtcp, and mouse mAsbt, human ASBT only showed reliable transport activity for 3alpha-

41 The bile acid responsiveness of human ASBT is unknown.

42 duce a negative feedback regulation of human ASBT via an FXR-mediated, SHP-dependent effect upon RAR/

43 the binding of specific inhibitors of human ASBT.

44 Inactivation of the human ASBT due to MTS modification of cysteine 270 was shown t

45 In conclusion, the human ASBT is positively regulated by retinoic acid.

46 -fos antisense treatment activated the human ASBT promoter 5-fold and not only abrogated interleukin-

47 Retinoic acid activated the human ASBT promoter fourfold.

48 The human ASBT promoter linked to a luciferase reporter was studie

49 nesis of an RAR/RXR cis element in the human ASBT promoter reduced its activity by 50% and eliminated

50 nsitivity to 2164U90, as seen with the human ASBT, even though it is identical to the mouse SBAT in t

51 brane transporter function by targeting IBAT/ASBT and NTCP, there is an array of potentially additive

52 rminal ileum and proximal renal tubule (IBAT/ASBT inhibitors) and basolateral (sinusoidal) BA uptake

53 s rats leads to specific reductions in ileal ASBT messenger RNA and protein levels, whereas c-jun and

54 Terminal ileal ASBT protein was reduced in murine pregnancy.

55 1, alpha-SMA, TGR5, NTCP, OATP1a1, and ileum ASBT and decreased liver IL-10, FXR, CAR, VDR, BSEP, MRP

56 ors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure o

57 hibitor and is accompanied by an increase in ASBT polyubiquitin conjugates and a reduced ASBT half-li

58 ression but led to a paradoxical increase in ASBT promoter activity.

59 demonstrate that TM1 plays a pivotal role in ASBT function and stability, thereby providing further i

60 nt-accessible and plays an important role in ASBT function and substrate translocation.

61 ntly reduced, and IL-1beta fails to increase ASBT turnover.

62 e inhibitor, causes time-dependent increased ASBT levels and increased intracellular accumulation of

63 d palmitic acid (100 mum for 15 h) increased ASBT function, whereas treatment with unsaturated oleic

64 le duct-ligated rats, we tested if increased ASBT activity (induced by secretin pretreatment) results

65 Consistent with increased ASBT promoting cholehepatic shunting, with secretin pret

66 life is markedly prolonged, IL-1beta-induced ASBT ubiquitination is significantly reduced, and IL-1be

67 with increased cholangiocyte apical membrane ASBT.

68 mologue of ASBT from Neisseria meningitidis (ASBT(NM)) at 2.2 A.

69 f a transporter from Neisseria meningitidis (ASBT(NM)) in complex with pantoate, a potential substrat

70 ASBT homologue from Neisseria meningitidis (ASBT(NM)) in detergent was reported recently, showing th

71 Human, rat, and mouse ASBT is inhibited by inflammatory cytokines via direct i

72 the rat ASBT which is identical to the mouse ASBT in this domain also had the high sensitivity to 216

73 ty to 2164U90 inhibition found for the mouse ASBT.

74 ntial therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 dia

75 he identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibi

76 30672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model o

77 and increased intracellular accumulation of ASBT.

78 er reporter, while paradoxical activation of ASBT was seen in c-fos-null mice.

79 -dependent effect upon RAR/RXR activation of ASBT.

80 R development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in

81 coimmunoprecipitation and colocalization of ASBT and ubiquitin.

82 ling capacity and high transport efficacy of ASBT-mediated absorption.

83 d developmental stage-specific expression of ASBT in the rat intestine correlated with the presence o

84 g in mice results in decreased expression of ASBT protein and mRNA.

85 xon-2 skipped, alternatively spliced form of ASBT, designated t-ASBT, expressed in rat cholangiocytes

86 rystal structure of a bacterial homologue of ASBT from Neisseria meningitidis (ASBT(NM)) at 2.2 A.

87 Inhibition of ASBT reduces BA pool size and retention of hydrophobic B

88 hypercholesterolaemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing

89 ylamino-benzanilide S1647 is an inhibitor of ASBT and SOAT.

90 5, a minimally absorbed, potent inhibitor of ASBT, providing, on average, 11 mg/kg/day of compound.

91 nsiderably lowered by specific inhibitors of ASBT, and ASBT is thus a target for hypercholesterolaemi

92 , which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents.

93 stochemistry revealed apical localization of ASBT in cholangiocytes in normal rat liver.

94 apture method, we found that the majority of ASBT (~80%) was S-acylated in ileal brush border membran

95 ology, we built a three-dimensional model of ASBT using an approach of homology-modeling and remote-t

96 S-acylation is involved in the modulation of ASBT function.

97 Prior studies suggested that ontogeny of ASBT is controlled in part by changes in messenger RNA (

98 egulated serine/threonine phosphorylation of ASBT protein at both Ser-335 and Thr-339.

99 2.7- and 0.2-kilobase 5'-flanking region of ASBT.

100 ies-specific negative feedback regulation of ASBT by bile acids is mediated by farnesoid X receptor v

101 -1beta (IL-1beta) induced down-regulation of ASBT is abrogated by a JNK inhibitor and is accompanied

102 Transcriptional regulation of ASBT is well described, whereas information on posttrans

103 ed the bile acid mediated down-regulation of ASBT.

104 nvolved in the transcriptional regulation of ASBT.

105 n-induced acute ileitis led to repression of ASBT in wild-type mice and in the transgenic rat ASBT pr

106 offset the bile acid mediated repression of ASBT promoter activity.

107 The bile acid responsiveness of ASBT is controversial.

108 plex with pantoate, a potential substrate of ASBT(NM).

109 e splicing changes the cellular targeting of ASBT, alters its functional properties, and provides a m

110 ignature motif (ALGMMPL) localized to TM3 of ASBT with as yet undetermined function.

111 The membrane topology of ASBT was initially scanned using a consensus topography

112 were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has bee

113 ved in exerting counterregulatory effects on ASBT mRNA stability.

114 ible for bile acid efflux in ileum and other ASBT-expressing tissues.

115 d in preclinical studies for pharmacological ASBT, NTCP, and/or SOAT inhibition.

116 Rat ASBT promoter transgenic, wild-type, and c-fos-null mice

117 fection studies of the human, mouse, and rat ASBT promoters and Northern analyses were performed in c

118 LRH-1 cis-elements between the mouse and rat ASBT promoters was associated with an interconversion of

119 Mouse but not rat ASBT promoter activity was repressed in Caco-2, but not

120 The same 3'UTR fragments of rat ASBT were incorporated into a beta-globin coding mRNA co

121 ains the 3' untranslated region (UTR) of rat ASBT.

122 SBT3-betaglobin containing 0.3 kb of the rat ASBT 3'UTR.

123 1 element regulates transcription of the rat ASBT gene.

124 In addition, the rat ASBT which is identical to the mouse ASBT in this domain

125 ssays revealed binding of HuR and TTP to rat ASBT 3'UTR.

126 in wild-type mice and in the transgenic rat ASBT promoter reporter, while paradoxical activation of

127 ential for unsaturated fatty acids to reduce ASBT function, which may be useful in disorders in which

128 ASBT polyubiquitin conjugates and a reduced ASBT half-life.

129 unsaturated oleic acid significantly reduced ASBT function.

130 tate (25 mum for 15 h) significantly reduced ASBT S-acylation, function, and levels on the plasma mem

131 scription factors c-Jun and c-Fos regulating ASBT expression.

132 zed ontogenic changes in rat ileal and renal ASBT expression.

133 translocation of c-fos, which then represses ASBT promoter activity via binding of the 3' AP-1 elemen

134 A3907 was a potent and selective ASBT inhibitor in vitro.

135 Secretin stimulated colchicine-sensitive ASBT translocation to the cholangiocyte plasma membrane

136 cells led to a 75% reduction in steady-state ASBT messenger RNA levels and a 78% reduction in human A

137 The systemic ASBT inhibitor A3907 improved experimental cholestatic d

138 rnatively spliced form of ASBT, designated t-ASBT, expressed in rat cholangiocytes, ileum, and kidney

139 tibodies detected the approximately 19 kDa t-ASBT polypeptide in rat cholangiocytes, ileum, and kidne

140 t studies in Xenopus oocytes revealed that t-ASBT can function as a bile acid efflux protein.

141 The t-ASBT was specifically localized to the basolateral domai

142 fected with green fluorescent protein-tagged ASBT and hemagglutinin-tagged ubiquitin, we demonstrated

143 xperimental cholestatic disease by targeting ASBT function at the intestinal, liver, and kidney level

144 degradation under basal conditions and that ASBT proteasome disposal is increased by IL-1beta due to

145 Protein turnover assays demonstrated that ASBT is an unstable and short-lived protein.

146 These results indicate that ASBT undergoes ubiquitin-proteasome degradation under ba

147 These studies not only show that ASBT expression is controlled at the level of mRNA stabi

148 tic acid (100 mum for 15 h) also showed that ASBT is S-acylated in 2BT cells.

149 The ASBT gene extends over 17 kilobases and contains five in

150 The ASBT inhibitors odevixibat, maralixibat, and elobixibat

151 The ASBT promoter contains 2 distinct cis AP-1 elements; the

152 The ASBT(NM) structure was captured with the substrate tauro

153 uctural and functional importance during the ASBT transport cycle.

154 using a well-characterized antibody for the ASBT demonstrated a 48-kD protein present only in apical

155 nsight into molecular mechanisms guiding the ASBT transport cycle with respect to substrate binding a

156 ase pair cis-element from the 3' site in the ASBT promoter imparts cytokine-mediated down-regulation

157 ctivated protein (AP)-1 site inactivates the ASBT promoter, whereas mutation of the 3' site abrogates

158 ation-deficient S335A and T339A mutants, the ASBT half-life is markedly prolonged, IL-1beta-induced A

159 transport function or the expression of the ASBT or the ILBP.

160 SHP repressed the activity of the ASBT promoter and reduced activation by retinoic acid.

161 necrosis factor repress the activity of the ASBT promoter in Caco-2 and intestinal epithelial cell-6

162 endent repression of LRH-1 activation of the ASBT promoter.

163 t analysis demonstrated that the size of the ASBT transcript was identical in NRC, freshly isolated c

164 orally administered A3907 distributed to the ASBT-expressing organs, that is, ileum, liver, and kidne

165 t in NRC whose sequence was identical to the ASBT.

166 the apical domain of cholangiocytes via the ASBT, and are consistent with the notion that cholangioc

167 es via direct interactions of c-fos with the ASBT promoter.

168 r 15 h) revealed that oleic acid attaches to ASBT, suggesting that unsaturated fatty acids may decrea

169 apical sodium dependent bile acid transport (ASBT)-mediated uptake of [(14)C]taurocholate (TC) in H14

170 odium-dependent bile acid uptake transporter ASBT (SLC10A2).

171 ical sodium-dependent bile acid transporter (ASBT) (SLC10A2), only expressed in the liver on the chol

172 ical sodium-dependent bile acid transporter (ASBT) and the ileal lipid-binding protein (ILBP) were as

173 ical sodium-dependent bile acid transporter (ASBT) by inflammatory cytokines in vitro and in vivo are

174 pical Na(+)-dependent bile acid transporter (ASBT) in bile formation is unknown.

175 ical sodium-dependent bile acid transporter (ASBT) in substrate interaction warranted examination of

176 ical sodium-dependent bile acid transporter (ASBT) in the rat is unaffected by bile salts, yet in the

177 e by an apical sodium-bile acid transporter (ASBT) inhibitor decreases ileal FGF15, enhances hepatic

178 al sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol withou

179 al sodium-codependent bile acid transporter (ASBT) inhibitors.

180 ical sodium-dependent bile acid transporter (ASBT) is crucial for the enterohepatic circulation of bi

181 ion and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and we

182 ical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastro

183 ical sodium-dependent bile acid transporter (ASBT), a key membrane protein involved in cholesterol ho

184 ical sodium-dependent bile acid transporter (ASBT), an ileal Na(+)-dependent transporter, plays the l

185 ical sodium-dependent bile acid transporter (ASBT), blocks progression of sclerosing cholangitis in m

186 ical sodium-dependent bile acid transporter (ASBT), effectively blocking ASBT's function in the small

187 ical sodium-dependent bile acid transporter (ASBT).

188 ical sodium-dependent bile acid transporter (ASBT).

189 by a Na(+)-dependent bile acid transporter (ASBT).

190 ical sodium-dependent bile acid transporter (ASBT, also known as SLC10A2).

191 ical sodium-dependent bile acid transporter (ASBT, SLC10A2) facilitates the enterohepatic circulation

192 ical sodium-dependent bile acid transporter (ASBT, SLC10A2) mediates intestinal, renal, and cholangio

193 ical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in

194 ical sodium-dependent bile acid transporter (ASBT=SLC10A2).

195 ased apical sodium-dependent BA transporter (ASBT) gene expression.

196 The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and sig

197 inal apical sodium-dependent BA transporter (ASBT).

198 xpression of the main bile acid transporter, ASBT, thus preventing bile acid reabsorption.

199 Quantification of bile acid transporter, ASBT-expressing neurons in the hypothalamus, revealed a

200 ter inhibition seen with the mouse wild type ASBT.

201 ite for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the d

202 evels in cholangiocytes to determine whether ASBT expression is regulated by ubiquitination and dispo

203 ction via a direct covalent interaction with ASBT.

204 l as in HEK293 cells stably transfected with ASBT (2BT cells).

205 In recent years, ASBT has attracted much interest as a potential drug tar