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Pregnancy Represses Induction of Efflux Transporters in Livers of Type I Diabetic Mice

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ABSTRACT

Purpose

To determine whether down-regulation of transcription factor signaling during pregnancy disrupts the induction of efflux transporters in type I diabetic mice.

Methods

Type I diabetes was induced in female C57BL/6 mice with multiple low dose intraperitoneal injections of streptozotocin (STZ) at least 2 weeks prior to mating with normoglycemic male mice. On gestation day 14, livers were collected from vehicle- and STZ-treated non-pregnant and pregnant mice for quantification of efflux transporter and transcription factor signaling.

Results

STZ treatment up-regulated expression of Mrp1-5, Mdr1, Abcg5, Abcg8, Bcrp, and Bsep mRNA and/or protein in the livers of non-pregnant mice. Interestingly, little to no change in transporter expression was observed in STZ-treated pregnant mice compared to vehicle- and STZ-treated non-pregnant mice.

Conclusions

This study demonstrates the opposing regulation of hepatobiliary efflux transporters in response to diabetes and pregnancy and points to PPARγ, Nrf2, and FXR as candidate pathways underlying the differential expression of transporters.

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Abbreviations

Abc:

ATP-binding cassette

Bsep:

bile salt export pump

Bcrp:

breast cancer resistance protein

CAR:

constitutive androstane receptor

Cyp:

cytochrome P450

FXR:

farnesoid x receptor

Mrp:

multidrug resistance-associated proteins

Mdr:

multidrug resistance proteins

Nqo1:

NAD(P)H quinone oxidoreductase 1

Nrf2:

nuclear factor E2-related factor 2

PPARγ:

peroxisome proliferator activated receptor gamma

PGC-1α:

PPARγ coactivator-1alpha

PXR:

pregnane X receptor

Shp:

short heterodimer protein

STZ:

streptozotocin

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors appreciate antibodies provided by Dr. Bruno Steiger (University Hospital, Zurich, Switzerland) and Dr. George Scheffer (VU Medical Center, Amsterdam, The Netherlands), and tissue collections performed by Myrna Trumbauer (Dept. of Pharmacology and Toxicology, Rutgers University). This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK080774] and the National Institute of Environmental Health Sciences [Grants ES020522, ES016042, ES005022], components of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey, USA

    Lauren M. Aleksunes, Eugenia Lin & Xia Wen

  2. Environmental and Occupational Health Sciences Institute, A Joint Institute of Robert Wood Johnson Medical School & Rutgers, Piscataway, New Jersey, USA

    Lauren M. Aleksunes & Xia Wen

  3. Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA

    Jialin Xu & Angela L. Slitt

  4. Department of Pathology, Merck Research Laboratories, Kenilworth, New Jersey, USA

    Michael J. Goedken

  5. Department of Pharmacology and Toxicology, Rutgers University, 170 Frelinghuysen Rd., Piscataway, New Jersey, 08854, USA

    Lauren M. Aleksunes

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  1. Lauren M. Aleksunes
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  2. Jialin Xu
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  4. Xia Wen
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Correspondence to Lauren M. Aleksunes.

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Aleksunes, L.M., Xu, J., Lin, E. et al. Pregnancy Represses Induction of Efflux Transporters in Livers of Type I Diabetic Mice. Pharm Res 30, 2209–2220 (2013). https://doi.org/10.1007/s11095-013-0981-z

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  • DOI: https://doi.org/10.1007/s11095-013-0981-z

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