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Tissue specific induction of p62/sqstm1 by farnesoid X receptor

Williams, JA and Thomas, AM and Li, G and Kong, B and Zhan, L and Inaba, Y and Xie, W and Ding, WX and Guo, GL (2012) Tissue specific induction of p62/sqstm1 by farnesoid X receptor. PLoS ONE, 7 (8).

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Abstract

Background: Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily and is a ligand-activated transcription factor essential for maintaining liver and intestinal homeostasis. FXR is protective against carcinogenesis and inflammation in liver and intestine as demonstrated by the development of inflammation and tumors in the liver and intestine of FXR knock-out mice. However, mechanisms for the protective effects of FXR are not completely understood. This study reports a novel role of FXR in regulating expression of Sqstm1, which encodes for p62 protein. p62 plays an important role in maintaining cellular homeostasis through selective autophagy and activating signal transduction pathways, such as NF-κB to support cell survival and caspase-8 to initiate apoptosis. FXR regulation of Sqstm1 may serve as a protective mechanism. Methods and Results: This study showed that FXR bound to the Sqstm1 gene in both mouse livers and ileums as determined by chromatin immunoprecipitation. In addition, FXR activation enhanced transcriptional activation of Sqstm1 in vitro. However, wild-type mice treated with GW4064, a synthetic FXR ligand, showed that FXR activation induced mRNA and protein expression of Sqstm1/p62 in ileum, but not in liver. Interestingly, FXR-transgenic mice showed induced mRNA expression of Sqstm1 in both liver and ileum compared to wild-type mice. Conclusions: Our current study has identified a novel role of FXR in regulating the expression of p62, a key factor in protein degradation and cell signaling. Regulation of p62 by FXR indicates tissue-specific and gene-dosage effects. Furthermore, FXR-mediated induction of p62 may implicate a protective mechanism of FXR. © 2012 Williams et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Williams, JA
Thomas, AM
Li, G
Kong, B
Zhan, L
Inaba, Y
Xie, Wwex6@pitt.eduWEX6
Ding, WX
Guo, GL
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorLobaccaro, Jean-Marc A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Center for Vaccine Research
Date: 27 August 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 8
DOI or Unique Handle: 10.1371/journal.pone.0043961
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Refereed: Yes
Other ID: NLM PMC3428273
PubMed Central ID: PMC3428273
PubMed ID: 22952826
Date Deposited: 02 Nov 2012 21:03
Last Modified: 29 Jan 2019 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/15894

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