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

Ma, Li; Jüttner, Moritz; Kullak‐Ublick, Gerd A.; Eloranta, Jyrki J.

doi:10.1152/ajpgi.00102.2011

Cited by 21 publications

(16 citation statements)

References 46 publications

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“…In an analysis of the main transporters expressed in intestine, P-gp and BCRP were ruled out due to the insignificant effect on efflux in the presence of GG918. The multidrug resistance-associated protein family (MRPs) are observed to transport drugs conjugated to glutathione, sulfate or glucuronide and a variety of endogenous compounds (25); the proton-coupled oligopeptide transporter 1 (PEPT1) mediates the cellular uptake of di/tripeptides and peptide-like drugs (26); the monocarboxylic acid transporter (MCT) is responsible for the absorption of short chain fatty and monocarboxylates (27); the apical sodium/bile acid co-transporter (ASBT) mediates bile acid absorption across the apical membranes (28). These transporters were also excluded because propranolol is not within their substrate specificity.…”

Section: Discussionmentioning

confidence: 99%

pH Dependent but not P-gp Dependent Bidirectional Transport Study of S-propranolol: The Importance of Passive Diffusion

et al. 2015

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Purpose Recent controversial publications, citing studies purporting to show that P-gp mediates the transport of propranolol, proposed that passive biological membrane transport is negligible. Based on the BDDCS, the extensively metabolized-highly permeable-highly soluble BDDCS class 1 drug, propranolol, shows a high passive permeability at concentrations unrestricted by solubility that can overwhelm any potential transporter effects. Here we reinvestigate the effects of passive diffusion and carrier-mediated transport on S-propranolol. Methods Bidirectional permeability and inhibition of efflux transport studies were carried out in MDCK, MDCK-MDR1 and Caco-2 cell lines at different concentrations. Transcellular permeability studies were conducted at different apical pHs in the rat jejunum Ussing chamber model and PAMPA system. Results S-propranolol exhibited efflux ratios lower than 1 in MDCK, MDCK-MDR1 and Caco-2 cells. No significant differences of Papp, B->A in the presence and absence of the efflux inhibitor GG918 were observed. However, an efflux ratio of 3.63 was found at apical pH 6.5 with significant decrease in Papp, A->B and increase in Papp, B->A compared to apical pH 7.4 in Caco-2 cell lines. The pH dependent permeability was confirmed in the Ussing chamber model. S-propranolol flux was unchanged during inhibition by verapamil and rifampin. Furthermore, pH dependent permeability was also observed in the PAMPA system. Conclusions S-propranolol does not exhibit active transport as proposed previously. The "false" positive efflux ratio can be explained by the pH partition theory. As expected, passive diffusion, but not active transport, plays the primary role in the permeability of the BDDCS class 1 drug propranolol.

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Section: Discussionmentioning

confidence: 99%

pH Dependent but not P-gp Dependent Bidirectional Transport Study of S-propranolol: The Importance of Passive Diffusion

et al. 2015

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“…A unique feature of the intestinal epithelium is its constant renewal controlled by the coordinated proliferation and differentiation of epithelial stem cells and progenitor cells in the base of the crypt (2). The highly dynamic status of the epithelium is regulated by a transcriptional network, which controls signaling pathways (3, 4), the abundance of critical proteins for solute and ion transport, and the absorption of nutrients (5-7). This network includes hepatocyte nuclear factor 1 alpha and beta (HNF1α/β), caudal-type homeobox 2 (CDX2), hepatocyte nuclear factor 4 alpha (HNF4α), and GATA family factors (8-11).…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte nuclear factor 1 coordinates multiple processes in a model of intestinal epithelial cell function

Yang

Kerschner

Harris

2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Mutations in hepatocyte nuclear factor 1 transcription factors (HNF1α/β) are associated with diabetes. These factors are well studied in the liver, pancreas and kidney, where they direct tissue-specific gene regulation. However, they also have an important role in the biology of many other tissues, including the intestine. We investigated the transcriptional network governed by HNF1 in an intestinal epithelial cell line (Caco2). We used chromatin immunoprecipitation followed by direct sequencing (ChIP-seq) to identify HNF1 binding sites genome-wide. Direct targets of HNF1 were validated using conventional ChIP assays and confirmed by siRNA-mediated depletion of HNF1, followed by RT-qPCR. Gene ontology process enrichment analysis of the HNF1 targets identified multiple processes with a role in intestinal epithelial cell function, including properties of the cell membrane, cellular response to hormones, and regulation of biosynthetic processes. Approximately 50% of HNF1 binding sites were also occupied by other members of the intestinal transcriptional network, including hepatocyte nuclear factor 4A (HNF4A), caudal type homeobox 2 (CDX2), and forkhead box A2 (FOXA2). Depletion of HNF1 in Caco2 cells increases FOXA2 abundance and decreases levels of CDX2, illustrating the coordinated activities of the network. These data suggest that HNF1 plays an important role in regulating intestinal epithelial cell function, both directly and through interactions with other intestinal transcription factors.

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“…As described above, and by others, Cdx members exhibit different transactivation potential on a number of target genes in tissue culture models [24], [25], [26], [27]. It is, however, unclear if these differences hold in vivo .…”

Section: Resultsmentioning

confidence: 77%

“…In contrast to these observations, a number of studies in tissue culture models suggest that Cdx1 and Cdx2 exhibit specificity in the intestine. For example, the Cdx target apical sodium-dependent bile acid transporter (ASBT) is preferentially regulated by Cdx2 [24]. Furthermore, the calcium channel MS4AI2 is responsive to Cdx2, but not Cdx1 [25], while the intestinal alkaline phosphatase gene is activated by Cdx1 and inhibited by Cdx2 [26].…”

Section: Introductionmentioning

confidence: 99%

Cdx1 and Cdx2 Exhibit Transcriptional Specificity in the Intestine

2013

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The caudal-related homeodomain transcription factors Cdx1 and Cdx2 are expressed in the developing endoderm with expression persisting into adulthood. Cdx1−/− mutants are viable and fertile and display no overt intestinal phenotype. Cdx2 null mutants are peri-implantation lethal; however, conditional mutation approaches have revealed that Cdx2 is required for patterning the intestinal epithelium and specification of the colon. Cdx2 is also necessary for homeostasis of the intestinal tract in the adult, where Cdx1 and Cdx2 appear to functionally overlap in the distal colon, but not during intestinal development. Cdx1 and Cdx2 exhibit complete overlap of expression in the intestine, although they differ in their relative levels, with Cdx1 maximal in the distal colon and Cdx2 peaking in the proximal cecum. Moreover, Cdx1 protein is graded along the crypt-villus axis, being abundant in the crypts and diminishing towards the villi. Cdx2 is expressed uniformly along this axis, but is differentially phosphorylated; the functional relevance of these expression domains and phosphorylation is currently unknown. Cdx1 and Cdx2 have been suggested to exhibit functional specificity in the intestinal tract. In the present study, using cell-based models, we found that relative to Cdx1, Cdx2 was significantly less potent at effecting a transcriptional response from the Cdx1 promoter, a known Cdx target gene. We subsequently assessed this relationship in vivo using a “gene swap” approach and found that Cdx2 cannot substitute for Cdx1 in this autoregulatory loop. This is in marked contrast with the ability of Cdx2 to support Cdx1 expression and function in paraxial mesoderm and vertebral patterning, thus providing novel in vivo evidence of context-dependent transcriptional specificity between these transcription factors.

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

Cited by 21 publications

References 46 publications

pH Dependent but not P-gp Dependent Bidirectional Transport Study of S-propranolol: The Importance of Passive Diffusion

pH Dependent but not P-gp Dependent Bidirectional Transport Study of S-propranolol: The Importance of Passive Diffusion

Hepatocyte nuclear factor 1 coordinates multiple processes in a model of intestinal epithelial cell function

Cdx1 and Cdx2 Exhibit Transcriptional Specificity in the Intestine

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