ライフサイエンスコーパス: ASBT

1 ASBT reclaims bile acids from the distal ileum via activ

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

26 The bile acid responsiveness of human ASBT is unknown.

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

28 the binding of specific inhibitors of human ASBT.

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

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

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

32 Retinoic acid activated the human ASBT promoter fourfold.

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

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

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

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

37 1, alpha-SMA, TGR5, NTCP, OATP1a1, and ileum ASBT and decreased liver IL-10, FXR, CAR, VDR, BSEP, MRP

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

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

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

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

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

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

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

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

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

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

48 with increased cholangiocyte apical membrane ASBT.

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

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

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

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

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

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

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

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

57 and increased intracellular accumulation of ASBT.

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

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

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

61 coimmunoprecipitation and colocalization of ASBT and ubiquitin.

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

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

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

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

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

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

68 5, a minimally absorbed, potent inhibitor of ASBT, providing, on average, 11 mg/kg/day of compound.

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

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

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

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

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

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

75 2.7- and 0.2-kilobase 5'-flanking region of ASBT.

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

77 -1beta (IL-1beta) induced down-regulation of ASBT is abrogated by a JNK inhibitor and is accompanied

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

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

80 nvolved in the transcriptional regulation of ASBT.

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

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

83 The bile acid responsiveness of ASBT is controversial.

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

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

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

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

88 ved in exerting counterregulatory effects on ASBT mRNA stability.

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

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

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

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

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

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

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

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

97 1 element regulates transcription of the rat ASBT gene.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

118 uctural and functional importance during the ASBT transport cycle.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

155 ter inhibition seen with the mouse wild type ASBT.

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

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

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