Down-regulation of mouse organic anion-transporting polypeptide 4 (Oatp4; Oatp1b2; Slc21a10) mRNA by lipopolysaccharide through the toll-like receptor 4 (TLR4)

Ning Li, Supratim Choudhuri, Nathan J Cherrington, Curtis D. Klaassen

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20 Citations (Scopus)

Abstract

Lipopolysaccharide (LPS) causes a systemic reaction known as sepsis, which is frequently associated with cholestasis. Many biological effects produced by LPS are thought to be mediated by Toll-like receptor 4 (TLR4). Organic anion-transporting polypeptide 4 (Oatp4; Slc21a10) mediates hepatic uptake of bile acids and other organic anions. The purpose of this study was to determine 1) whether LPS decreases Oatp4 mRNA levels; 2) the role of TLR4 in the LPS-induced down-regulation of Oatp4; and 3) the time course of serum concentrations of tumor necrosis factor α, interleukin (IL) 1β, and IL-6 after LPS administration. For the dose-response study, LPS (1 mg/kg i.p.) produced a significant decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice, and higher doses produced slightly greater decreases. However, none of the doses of LPS examined significantly decreased Oatp4 mRNA levels in TLR4-mutant C3H/HeJ mice. For the time-response study, LPS (5 mg/kg i.p.) produced a rapid decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice. The maximal decrease in Oatp4 mRNA levels (80%) was observed 12 h after LPS administration and returned to control levels thereafter. In contrast, LPS did not produce a significant decrease in Oatp4 mRNA levels at any time in TLR4-mutant C3H/HeJ mice. These findings demonstrate that LPS decreases Oatp4 mRNA levels in mice, and the decrease is mediated through TLR4.

Original languageEnglish (US)
Pages (from-to)1265-1271
Number of pages7
JournalDrug Metabolism and Disposition
Volume32
Issue number11
StatePublished - Nov 2004

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Toll-Like Receptor 4
Anions
Lipopolysaccharides
Down-Regulation
Messenger RNA
Peptides
Inbred C3H Mouse
Cholestasis
Level control
Bile Acids and Salts
Interleukin-1
Interleukin-6
Sepsis
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Down-regulation of mouse organic anion-transporting polypeptide 4 (Oatp4; Oatp1b2; Slc21a10) mRNA by lipopolysaccharide through the toll-like receptor 4 (TLR4). / Li, Ning; Choudhuri, Supratim; Cherrington, Nathan J; Klaassen, Curtis D.

In: Drug Metabolism and Disposition, Vol. 32, No. 11, 11.2004, p. 1265-1271.

Research output: Contribution to journalArticle

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