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Modulation of sulfur assimilation metabolic toxicity overcomes anemia and hemochromatosis in mice.

Publication ,  Journal Article
Hale, AT; Brown, RE; Luka, Z; Hudson, BH; Matta, P; Williams, CS; York, JD
Published in: Adv Biol Regul
May 2020

Sulfur assimilation is an essential metabolic pathway that regulates sulfation, amino acid metabolism, nucleotide hydrolysis, and organismal homeostasis. We recently reported that mice lacking bisphosphate 3'-nucleotidase (BPNT1), a key regulator of sulfur assimilation, develop iron-deficiency anemia (IDA) and anasarca. Here we demonstrate two approaches that successfully reduce metabolic toxicity caused by loss of BPNT1: 1) dietary methionine restriction and 2) overproduction of a key transcriptional regulator hypoxia inducible factor 2α (Hif-2a). Reduction of methionine in the diet reverses IDA in mice lacking BPNT1, through a mechanism of downregulation of sulfur assimilation metabolic toxicity. Gaining Hif-2a acts through a different mechanism by restoring iron homeostatic gene expression in BPNT1 deficient mouse intestinal organoids. Finally, as loss of BPNT1 impairs expression of known genetic modifiers of iron-overload, we demonstrate that intestinal-epithelium specific loss of BPNT1 attenuates hepatic iron accumulation in mice with homozygous C282Y mutations in homeostatic iron regulator (HFEC282Y), the most common cause of hemochromatosis in humans. Overall, our study uncovers genetic and dietary strategies to overcome anemia caused by defects in sulfur assimilation and identifies BPNT1 as a potential target for the treatment of hemochromatosis.

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Published In

Adv Biol Regul

DOI

EISSN

2212-4934

Publication Date

May 2020

Volume

76

Start / End Page

100694

Location

England

Related Subject Headings

  • Sulfur
  • Signal Transduction
  • Organoids
  • Nucleotidases
  • Mutation
  • Mice, Knockout
  • Mice
  • Methionine
  • Male
  • Liver
 

Citation

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Hale, A. T., Brown, R. E., Luka, Z., Hudson, B. H., Matta, P., Williams, C. S., & York, J. D. (2020). Modulation of sulfur assimilation metabolic toxicity overcomes anemia and hemochromatosis in mice. Adv Biol Regul, 76, 100694. https://doi.org/10.1016/j.jbior.2020.100694
Hale, Andrew T., Rachel E. Brown, Zigmund Luka, Benjamin H. Hudson, Pranathi Matta, Christopher S. Williams, and John D. York. “Modulation of sulfur assimilation metabolic toxicity overcomes anemia and hemochromatosis in mice.Adv Biol Regul 76 (May 2020): 100694. https://doi.org/10.1016/j.jbior.2020.100694.
Hale AT, Brown RE, Luka Z, Hudson BH, Matta P, Williams CS, et al. Modulation of sulfur assimilation metabolic toxicity overcomes anemia and hemochromatosis in mice. Adv Biol Regul. 2020 May;76:100694.
Hale, Andrew T., et al. “Modulation of sulfur assimilation metabolic toxicity overcomes anemia and hemochromatosis in mice.Adv Biol Regul, vol. 76, May 2020, p. 100694. Pubmed, doi:10.1016/j.jbior.2020.100694.
Hale AT, Brown RE, Luka Z, Hudson BH, Matta P, Williams CS, York JD. Modulation of sulfur assimilation metabolic toxicity overcomes anemia and hemochromatosis in mice. Adv Biol Regul. 2020 May;76:100694.
Journal cover image

Published In

Adv Biol Regul

DOI

EISSN

2212-4934

Publication Date

May 2020

Volume

76

Start / End Page

100694

Location

England

Related Subject Headings

  • Sulfur
  • Signal Transduction
  • Organoids
  • Nucleotidases
  • Mutation
  • Mice, Knockout
  • Mice
  • Methionine
  • Male
  • Liver