title: Indoxyl sulfate suppresses hepatic fetuin-A expression via the aryl hydrocarbon receptor in HepG2 cells.
abstract: BACKGROUND
  Fetuin-A is a liver-derived circulating protein that has potent calcification-inhibitory activity. Uraemic patients exhibit decreased serum fetuin-A levels, increased vascular calcification and elevated cardiovascular mortality. Because the mechanisms for fetuin-A deficiency are unknown, we hypothesized that some uraemic toxins suppressed hepatic fetuin-A production, which resulted in accelerated vascular calcification and poor outcome. Among these potential candidates, indoxyl sulfate (IS) has highly toxic properties.
  
  
  METHODS
  We examined the direct effects of IS on hepatic fetuin-A expression using the human hepatoma HepG2 cell line.
  
  
  RESULTS
  IS, but not p-cresyl sulfate, suppressed the mRNA and protein expression of fetuin-A in a dose- and time-dependent manner. As reported previously, IS stimulated p38 MAPK phosphorylation and reactive oxygen species (ROS) production, although the knockdown of p38 and inhibition of ROS generation had no effect on IS-induced fetuin-A suppression. Then, because IS is a potent endogenous ligand of the aryl hydrocarbon receptor (AhR), we assessed whether IS suppresses fetuin-A production via AhR. The knockdown of AhR prevented IS-induced fetuin-A suppression. However, some attention should be paid to no effect of IS on fetuin-A expression in mouse and human primary cultured hepatocytes.
  
  
  CONCLUSIONS
  These findings suggest that IS could suppress hepatic fetuin-A expression by activating AhR, suggesting a relationship between uraemia and fetuin-A deficiency.
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Ochi
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Nakatani
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Emoto
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Morioka
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Koka
authors.initials: K
authors.lastname: Motoyama
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukumoto
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Imanishi
authors.affiliation: Department of Geriatrics and Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shoji
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ishimura
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Inaba
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007200:Indican / Q000494:pharmacology*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D060749:alpha-2-HS-Glycoprotein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D060749:alpha-2-HS-Glycoprotein; D048051:p38 Mitogen-Activated Protein Kinases; D007200:Indican
keywords: AHSG; fetuin-A; hepatocyte; indoxyl sulfate