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Metabolic signaling functions of the heme oxygenase/CO system in metabolic diseases

Cellular & Molecular Immunology volume 15, pages 1085–1087 (2018)Cite this article

Immunometabolism is the intersection of immunology and metabolism. The heme oxygenase (HO)-1 and carbon monoxide (CO) (HO-1/CO) system can be induced by various stresses, including infection, and its function is to relieve stresses such as oxidative and inflammatory reactions. Here we demonstrate that the HO-1/CO system is intimately involved in the beneficial modulation of metabolic pathways via the production of ATF4 through an integrative stress response.

Although heme is vital for the progression of metabolic processes, it is also dangerous when, in excess amounts, it is released from intracellular heme-containing proteins, including hemoglobin. The released heme, or free heme, may cause oxidative and inflammatory injury associated with the pathologies of diverse conditions. Thus, it is urgent to remove excess free heme from sites of injury. The microsomal enzyme heme oxygenase (HO) catalyzes the first and rate-limiting step in the oxidative degradation of heme to produce CO, ferrous iron (Fe2+), and biliverdin (BV). Subsequently, BV is converted into bilirubin by a BV reductase, and the ferrous iron is rapidly sequestered by ferritin and recycled for heme synthesis. An inducible form of the two HO isozymes, HO-1, which is expressed under various pathological conditions, can metabolize a large amount of heme to produce high concentrations of its products that cause medically interesting biological effects. HO-1 expression is caused not only because of its substrate, free heme, but also because of a wide variety of pro-inflammatory stimuli, suggesting that HO-1, in addition to its fundamental role in heme degradation, plays other important roles in the resolution of inflammation. The biological action of HO-derived carbon monoxide (CO) is substantiated by the pharmacological effects observed when this gas is applied exogenously to in vitro and in vivo systems. In this regard, this review focused on the modulation of metabolism by CO, as well as inflammation and its roles in immunometabolism.

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References

  1. Jamal Uddin, M. et al. IRG1 induced by heme oxygenase-1/carbon monoxide inhibits LPS-mediated sepsis and pro-inflammatory cytokine production. Cell. Mol. Immunol. 13, 170–179 (2016).

    Article  CAS  Google Scholar 

  2. Burgess, A. et al. Adipocyte heme oxygenase-1 induction attenuates metabolic syndrome in both male and female obese mice. Hypertension 56, 1124–1130 (2010).

    Article  CAS  Google Scholar 

  3. Wegiel, B. et al. Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth. Cancer Res. 73, 7009–7021 (2013).

    Article  CAS  Google Scholar 

  4. Zuckerbraun, B. S. et al. Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J. 21, 1099–1106 (2007).

    Article  CAS  Google Scholar 

  5. Liu, L., Wise, D. R., Diehl, J. A. & Simon, M. C. Hypoxic reactive oxygen species regulate the integrated stress response and cell survival. J. Biol. Chem. 283, 31153–31162 (2008).

    Article  CAS  Google Scholar 

  6. Verfaillie, T. et al. PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ. 19, 1880–1891 (2012).

    Article  CAS  Google Scholar 

  7. Ding, B. et al. Sestrin2 is induced by glucose starvation via the unfolded protein response and protects cells from non-canonical necroptotic cell death. Sci. Rep. 6, 22538 (2016).

    Article  CAS  Google Scholar 

  8. Kim, K. H. et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19, 83–92 (2013).

    Article  CAS  Google Scholar 

  9. Dennis, M. D., McGhee, N. K., Jefferson, L. S. & Kimball, S. R. Regulated in DNA damage and development 1 (REDD1) promotes cell survival during serum deprivation by sustaining repression of signaling through the mechanistic target of rapamycin in complex 1 (mTORC1). Cell Signal. 25, 2709–2716 (2013).

    Article  CAS  Google Scholar 

  10. Kim, K. M. et al. Carbon monoxide induces heme oxygenase-1 via activation of protein kinase R-like endoplasmic reticulum kinase and inhibits endothelial cell apoptosis triggered by endoplasmic reticulum stress. Circ. Res. 101, 919–927 (2007).

    Article  CAS  Google Scholar 

  11. , H. J. et al. Carbon monoxide protects against hepatic steatosis in mice by inducing sestrin-2 via the PERK-eIF2alpha-ATF4 pathway. Free Radic. Biol. Med. 110, 81–91 (2017).

    Article  CAS  Google Scholar 

  12. Xu, J. et al. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models–association with liver and adipose tissue effects. Am. J. Physiol. Endocrinol. Metab. 297, E1105–E1114 (2009).

    Article  CAS  Google Scholar 

  13. Joe, Y. et al. FGF21-induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway. FASEB J. 32, 2630–2643 (2018).

    Article  Google Scholar 

  14. Gu, Y. et al. MLN4924, an NAE inhibitor, suppresses AKT and mTOR signaling via upregulation of REDD1 in human myeloma cells. Blood 123, 3269–3276 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A6A1030318).

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  1. Department of Biological Sciences, University of Ulsan, Ulsan, South Korea

    Hyo Jeong Kim, Yeonsoo Joe & Hun Taeg Chung

  2. Tumor Microenvironment Global Core Research Center, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea

    Young-Joon Surh

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Correspondence to Hyo Jeong Kim.

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Kim, H.J., Joe, Y., Surh, YJ. et al. Metabolic signaling functions of the heme oxygenase/CO system in metabolic diseases. Cell Mol Immunol 15, 1085–1087 (2018). https://doi.org/10.1038/s41423-018-0045-8

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