Regulation of transporter expression in mouse liver, kidney, and intestine during extrahepatic cholestasis

Angela L. Slitt, Katryn Allen, Jennifer Morrone, Lauren M. Aleksunes, Chuan Chen, Jonathan M. Maher, José E. Manautou, Nathan J. Cherrington, Curtis D. Klaassen

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

It is hypothesized that during cholestasis, the liver, kidney, and intestine alter gene expression to prevent BA accumulation; enhance urinary excretion of BA; and decrease BA absorption, respectively. To test this hypothesis, mice were subjected to either sham or bile-duct ligation (BDL) surgery and liver, kidney, duodenum, ileum, and serum samples were collected at 1, 3, 7, and 14 days after surgery. Serum total BA concentrations were 1-5 μmol/l in sham-operated mice and were elevated at 1, 3, 7, and 14 days after BDL, respectively. BDL decreased liver Ntcp, Oatp1a1, 1a5, and 1b2 mRNA expression and increased Bsep, Oatp1a4, and Mrp1-5 mRNA levels. In kidney, BDL decreased Oatp1a1 and increased Mrp1-5 mRNA levels. In intestine, BDL increased Mrp3 and Ibat mRNA levels in ileum. BDL increased Mrp1, 3, 4, and 5 protein expression in mouse liver. These data indicate that the compensatory regulation of transporters in liver, kidney, and intestine is unable to fully compensate for the loss of hepatic BA excretion because serum BA concentration remained elevated after 14 days of BDL. Additionally, hepatic and renal Oatp and Mrp genes are regulated similarly during extrahepatic cholestasis, and may suggest that transporter expression is regulated not to remove bile constituents from the body, but instead to remove bile constituents from tissues.

Original languageEnglish (US)
Pages (from-to)637-647
Number of pages11
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1768
Issue number3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Keywords

  • Bile salt export pump
  • Bile-duct ligation
  • Cholestasis
  • Multidrug resistance-associated protein
  • Organic anion transporting polypeptide
  • Transporter

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

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  • Cite this

    Slitt, A. L., Allen, K., Morrone, J., Aleksunes, L. M., Chen, C., Maher, J. M., Manautou, J. E., Cherrington, N. J., & Klaassen, C. D. (2007). Regulation of transporter expression in mouse liver, kidney, and intestine during extrahepatic cholestasis. Biochimica et Biophysica Acta - Biomembranes, 1768(3), 637-647. https://doi.org/10.1016/j.bbamem.2006.10.008