title: Hemopexin-dependent heme uptake via endocytosis regulates the Bach1 transcription repressor and heme oxygenase gene activation.
abstract: BACKGROUND
  Intracellular heme plays versatile roles in a variety of physiological processes including mitochondrial respiration. Heme also induces the expression of genes such as heme oxygenase-1 (HO-1) by inactivating the transcription repressor Bach1 through direct binding. However, the source of heme for the regulation of the Bach1-HO-1 axis has been unclear. Considering that extracellular heme exists as a complex with hemopexin (Hx) in serum under the physiological conditions, heme-Hx complex may deliver heme for the gene regulation.
  
  
  METHODS
  Using a mammalian expression system, high secretory recombinant Hx (rHx) was developed. We examined the effects of rHx-bound heme on HO-1 expression and Bach1 in Hepa-1c1c7 liver cells and THP-1 macrophage cells. We investigated the uptake pathway of rHx-bound heme by treating cells with chlorpromazine (CPZ).
  
  
  RESULTS
  rHx-bound heme induced the expression of HO-1 and decreased the level of Bach1 protein. CPZ inhibited the induction of the HO-1 expression by rHx-bound heme.
  
  
  CONCLUSIONS
  rHx-bound heme was internalized into the cells via endocytosis, resulting in HO-1 expression and inactivation of Bach1.
  
  
  CONCLUSIONS
  The Bach1-dependent repression of the HO-1 expression is under the control of the Hx-dependent uptake of extracellular heme. Heme may regulate Bach1 as an extracellular signaling molecule.
authors.affiliation: Department of Biochemistry, and Center for Regulatory Epigenome and Disease, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; CREST, Japan Science and Technology Agency, Sendai 980-8575, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hada
authors.affiliation: Faculty of Biology-Oriented Science and Technology, Kinki University, Nishimitani, Kinokawashi, Wakayama 649-6493, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Shiraki
authors.affiliation: Department of Biochemistry, and Center for Regulatory Epigenome and Disease, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Watanabe-Matsui
authors.affiliation: Department of Biochemistry, and Center for Regulatory Epigenome and Disease, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; CREST, Japan Science and Technology Agency, Sendai 980-8575, Japan. Electronic address: igarashi@med.tohoku.ac.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002746:Chlorpromazine / Q000494:pharmacology; D004705:Endocytosis / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D057809:HEK293 Cells; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006466:Hemopexin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D012119:Respiration / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D006418:Heme; D006466:Hemopexin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D002746:Chlorpromazine
keywords: Bach1; Endocytosis; Heme; Heme oxygenase-1; Hemopexin; Oxidative stress