title: Tissue specific induction of p62/Sqstm1 by farnesoid X receptor.
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.
  
  
  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.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Williams
authors.forename: Ann M
authors.initials: AM
authors.lastname: Thomas
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.forename: Le
authors.initials: L
authors.lastname: Zhan
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017930:Genes, Reporter / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D008156:Luciferases; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000071456:Sequestosome-1 Protein; D000099150:Receptor, Farnesoid X-Activated; C099718:SQSTM1 protein, human; C101343:Sqstm1 protein, mouse