Modulation of farnesoid X receptor results in post-translational modification of poly (ADP-ribose) polymerase 1 in the liver

Yan Zhu, Guodong Li, Yafeng Dong, Helen H. Zhou, Bo Kong, Lauren M. Aleksunes, Jason R. Richardson, Fei Li, Grace L. Guo

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Abstract

The farnesoid X receptor (FXR) is a bile acid-activated transcription factor belonging to the nuclear receptor superfamily. FXR deficiency in mice results in cholestasis, metabolic disorders, and tumorigenesis in liver and intestine. FXR is known to contribute to pathogenesis by regulating gene transcription; however, changes in the post-transcriptional modification of proteins associated with FXR modulation have not been determined. In the current study, proteomic analysis of the livers of wild-type (WT) and FXR knockout (FXR-KO) mice treated with a FXR synthetic ligand or vehicle was performed. The results identified five proteins as novel FXR targets. Since FXR deficiency in mice leads to liver tumorigenesis, poly (ADP-ribose) polymerase family, member 1 (Parp1) that is important for DNA repair, was validated in the current study by quantitative real-time PCR, and 1- and 2-dimensional gel electrophoresis/western blot. The results showed that Parp1 mRNA levels were not altered by FXR genetic status or by agonist treatment. However, total Parp1 protein levels were increased in FXR-KO mice as early as 3. month old. Interestingly, total Parp1 protein levels were increased in WT mice in an age-dependent manner (from 3 to 18. months), but not in FXR-KO mice. Finally, activation of FXR in WT mice resulted in reduction of phosporylated Parp1 protein in the liver without affecting total Parp1 protein levels. In conclusion, this study reveals that FXR genetic status and agonist treatment affects basal levels and phosphorylation state of Parp1, respectively. These alterations, in turn, may be associated with the hepatobiliary alterations observed in FXR-KO mice and participate in FXR agonist-induced protection in the liver.

Original languageEnglish (US)
Pages (from-to)260-266
Number of pages7
JournalToxicology and Applied Pharmacology
Volume266
Issue number2
DOIs
StatePublished - Jan 5 2013

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All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Keywords

  • Farnesoid X receptor
  • Mice
  • Nuclear receptor
  • Parp1
  • Post-translational modification
  • Proteomics

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