Regulation of the gene encoding the intestinal bile acid transporter ASBT by the caudal-type homeobox proteins CDX1 and CDX2

2012 ◽  
Vol 302 (1) ◽  
pp. G123-G133 ◽  
Author(s):  
Li Ma ◽  
Moritz Jüttner ◽  
Gerd A. Kullak-Ublick ◽  
Jyrki J. Eloranta
Keyword(s):  
Transcription Factors ◽  
Bile Acid ◽  
Intestinal Cells ◽  
Mobility Shift ◽  
Gene Encoding ◽  
Aberrant Expression ◽  
Bile Acid Transporter ◽  
Acid Transporter ◽  
Differentiation And Proliferation

The apical sodium-dependent bile acid transporter (ASBT) is expressed abundantly in the ileum and mediates bile acid absorption across the apical membranes. Caudal-type homeobox proteins CDX1 and CDX2 are transcription factors that regulate genes involved in intestinal epithelial differentiation and proliferation. Aberrant expression of both ASBT and CDXs in Barrett's esophagus (BE) prompted us to study, whether the expression of the ASBT gene is regulated by CDXs. Short interfering RNA-mediated knockdown of CDXs resulted in reduced ASBT mRNA expression in intestinal cells. CDXs strongly induced the activity of the ASBT promoter in reporter assays in esophageal and intestinal cells. Nine CDX binding sites were predicted in silico within the ASBT promoter, and binding of CDXs to six of them was verified in vitro and within living cells by electrophoretic mobility shift assays and chromatin immunoprecipitation assays, respectively. RNAs were extracted from esophageal biopsies from 20 BE patients and analyzed by real-time PCR. Correlation with ASBT expression was found for CDX1, CDX2, and HNF-1α in BE biopsies. In conclusion, the human ASBT promoter is activated transcriptionally by CDX1 and CDX2. Our finding provides a possible explanation for the reported observation that ASBT is aberrantly expressed in esophageal metaplasia that also expresses CDX transcription factors.

scholarly journals Hepatitis D Virus Entry Inhibitors Based on Repurposing Intestinal Bile Acid Reabsorption Inhibitors

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 666
Author(s):  
Michael Kirstgen ◽  
Kira Alessandra Alicia Theresa Lowjaga ◽  
Simon Franz Müller ◽  
Nora Goldmann ◽  
Felix Lehmann ◽  
...  
Keyword(s):  
Bile Acid ◽  
Taurocholic Acid ◽  
Hek293 Cells ◽  
Acid Uptake ◽  
Hepatitis D ◽  
Entry Inhibitors ◽  
Ic50 Values ◽  
Bile Acid Transporter ◽  
Acid Transporter

Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as high-affinity hepatic entry receptor for the Hepatitis B and D viruses (HBV/HDV) opened the field for target-based development of cell-entry inhibitors. However, most of the HBV/HDV entry inhibitors identified so far also interfere with the physiological bile acid transporter function of NTCP. The present study aimed to identify more virus-selective inhibitors of NTCP by screening of 87 propanolamine derivatives from the former development of intestinal bile acid reabsorption inhibitors (BARIs), which interact with the NTCP-homologous intestinal apical sodium-dependent bile acid transporter (ASBT). In NTCP-HEK293 cells, the ability of these compounds to block the HBV/HDV-derived preS1-peptide binding to NTCP (virus receptor function) as well as the taurocholic acid transport via NTCP (bile acid transporter function) were analyzed in parallel. Hits were subsequently validated by performing in vitro HDV infection experiments in NTCP-HepG2 cells. The most potent compounds S985852, A000295231, and S973509 showed in vitro anti-HDV activities with IC50 values of 15, 40, and 70 µM, respectively, while the taurocholic acid uptake inhibition occurred at much higher IC50 values of 24, 780, and 490 µM, respectively. In conclusion, repurposing of compounds from the BARI class as novel HBV/HDV entry inhibitors seems possible and even enables certain virus selectivity based on structure-activity relationships.

scholarly journals Ileal bile acid transporter inhibition, CYP7A1 induction, and antilipemic action of 264W94

2002 ◽  
Vol 43 (8) ◽  
pp. 1320-1330 ◽  
Author(s):  
Carolyn Root ◽  
Chari D. Smith ◽  
Scott S. Sundseth ◽  
Heather M. Pink ◽  
Joan G. Wilson ◽  
...  
Keyword(s):  
Bile Acid ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Membrane Vesicles ◽  
Human Model ◽  
Diurnal Fluctuation ◽  
Bile Acid Transporter ◽  
Acid Transporter

264W94 was designed to inhibit the ileal bile acid transporter (IBAT). Evaluated in vitro, 264W94 dose-dependently inhibited sodium-dependent uptake of 10 μM [3H]taurocholic acid (TC) by rat and monkey brush border membrane vesicles with IC50s of 0.24 μM and 0.41 μM, and had a competitive profile with Ki of 0.2 μM against TC in Chinese hamster ovary cells expressing human IBAT. In distal ileum in situ, 1–10 μM of 264W94 rapidly decreased uptake of 3mM TC by 24–39%, with corresponding decreases in biliary recovery. In rats and mice in vivo, oral 264W94 decreased absorption of TC analog, 23,25-75Se-homocholic acid taurine (75SeHCAT; quantitated in feces), with ED30 of 0.02 mg/kg bid. 75SeHCAT traced through the GI-tract revealed that peak (97%) inhibition of 75SeHCAT absorption by the distal quarter of small intestine occurred at 4 h after single dose of 264W94 (0.1 mg/kg). Inhibition of IBAT by 264W94 in rats was associated with compensatory, same-day, 4-fold induction of hepatic cholesterol 7α-hydroxylase (CYP7A1) activity, exhibiting normal diurnal fluctuation for 3 days of dosing. In diet induced hypercholesterolemic rats, 264W94 (0.03–1.0 mg/kg bid) dose-dependently reduced serum LDL+VLDL cholesterol up to 61%.In conclusion, 264W94 is a potent new cholesterol lowering agent that acts through inhibition of IBAT and exhibits activity in a human model.

scholarly journals A Variant of the SLC10A2 Gene Encoding the Apical Sodium-Dependent Bile Acid Transporter Is a Risk Factor for Gallstone Disease

PLoS ONE ◽  
2009 ◽  
Vol 4 (10) ◽  
pp. e7321 ◽  
Author(s):  
Olga Renner ◽  
Simone Harsch ◽  
Elke Schaeffeler ◽  
Stefan Winter ◽  
Matthias Schwab ◽  
...  
Keyword(s):  
Risk Factor ◽  
Bile Acid ◽  
Gallstone Disease ◽  
Gene Encoding ◽  
Sodium Dependent ◽  
Bile Acid Transporter ◽  
Acid Transporter ◽  
Slc10a2 Gene

Induction of sodium-dependent bile acid transporter messenger RNA, protein, and activity in rat ileum by cholic acid

1997 ◽  
Vol 113 (5) ◽  
pp. 1599-1608 ◽  
Author(s):  
RT Stravitz ◽  
AJ Sanyal ◽  
WM Pandak ◽  
ZR Vlahcevic ◽  
JW Beets ◽  
...  
Keyword(s):  
Bile Acid ◽  
Cholic Acid ◽  
Messenger Rna ◽  
Rat Ileum ◽  
Sodium Dependent ◽  
Bile Acid Transporter ◽  
Acid Transporter
Sign in / Sign up

Export Citation Format

Share Document