Hemopexin-dependent heme uptake via endocytosis regulates the Bach1 transcription repressor and heme oxygenase gene activation

Hiroshi Hada, Takuma Shiraki, Miki Watanabe-Matsui, Kazuhiko Igarashi

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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. Conclusion rHx-bound heme was internalized into the cells via endocytosis, resulting in HO-1 expression and inactivation of Bach1. General significance 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.

Original languageEnglish
Pages (from-to)2351-2360
Number of pages10
JournalBiochimica et Biophysica Acta - General Subjects
Volume1840
Issue number7
DOIs
Publication statusPublished - 2014 Jul

Keywords

  • Bach1
  • Endocytosis
  • Heme
  • Heme oxygenase-1
  • Hemopexin
  • Oxidative stress

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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