Decreased apoptosis during CAR-mediated hepatoprotection against lithocholic acid-induced liver injury in mice

Lisa D. Beilke, Lauren M. Aleksunes, Erik R. Olson, David G. Besselsen, Curtis D. Klaassen, Katerina Dvorak, Nathan J. Cherrington

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of hepatoprotection. CAR+/+ (WT) and CAR-/- (CAR-null) mice were pre-treated with compounds known to activate CAR prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Pre-treatment with the CAR activators phenobarbital (PB) and TCPOBOP (TC), as well as the non-CAR activator pregnenolone 16α-carbontrile (PCN), protected against LCA-induced liver injury in WT mice, whereas liver injury was more extensive without CAR (CAR-null). Unexpectedly, expression of anti-apoptotic Mcl-1 and Bcl-xL was not increased in hepatoprotected mice. Compared to unprotected groups, apoptosis was decreased in hepatoprotected mice as evidenced by the absence of cleaved caspase 3 (cCasp3). In contrast to the cytoplasmic localization in the injured livers (LCA and oltipraz), Mcl-1 protein was localized in the nucleus of hepatoprotected livers to potentially promote cell survival. This study demonstrates that although apoptosis is reduced in hepatoprotected mice pre-treated with CAR and non-CAR activators; hepatoprotection is not directly a result of CAR-induced Mcl-1 expression.

Original languageEnglish (US)
Pages (from-to)38-44
Number of pages7
JournalToxicology letters
Volume188
Issue number1
DOIs
StatePublished - Jul 10 2009

Keywords

  • Apoptosis
  • Bile acid
  • CAR
  • Cholestasis
  • Liver
  • Nuclear receptors

ASJC Scopus subject areas

  • Toxicology

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