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Responses to Hypoxia: How Fructose Metabolism and Hypoxia-Inducible Factor-1a Pathways Converge in Health and Disease

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Abstract

Purpose of Review

Oxygen is critical for the high output of energy (adenosine triphosphate) generated by oxidative phosphorylation in the mitochondria, and when oxygen delivery is impaired due to systemic hypoxia, impaired or reduced delivery of red blood cells, or from local ischemia, survival processes are activated.

Recent Findings

One major mechanism is the activation of hypoxia-inducible factors (HIFs) that act to reduce oxygen needs by blocking mitochondrial function and stimulating glucose uptake and glycolysis while also stimulating red blood cell production and local angiogenesis. Recently, endogenous fructose production with uric acid generation has also been shown to occur in hypoxic and ischemic tissues where it also appears to drive the same functions, and indeed, there is evidence that many of hypoxia-inducible factors effects may be mediated by the stimulation of fructose production and metabolism. Unfortunately, while being acutely protective, these same systems in overdrive lead to chronic inflammation and disease and may also be involved in the development of metabolic syndrome and related disease. The benefit of SGLT2 inhibitors may act in part by reducing the delivery of glucose with the stimulation of fructose formation, thereby allowing a conversion from the glycolytic metabolism to one involving mitochondrial metabolism.

Summary

The use of hypoxia-inducible factor stabilizers is expected to aid the treatment of anemia but, in the long-term, could potentially lead to worsening cardiovascular and metabolic outcomes. We suggest more studies are needed on the use of these agents.

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Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey

    Mehmet Kanbay

  2. Department of Medicine, Koc University School of Medicine, Istanbul, Turkey

    Alara Altıntas, Furkan Yavuz & Sidar Copur

  3. Department of Cardio-Renal Physiopathology, National Institute of Cardiology Ignacio Chavez, Mexico City, Mexico

    Laura G. Sanchez-Lozada

  4. Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Miguel A. Lanaspa & Richard J. Johnson

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  1. Mehmet Kanbay
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  2. Alara Altıntas
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  3. Furkan Yavuz
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  4. Sidar Copur
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  5. Laura G. Sanchez-Lozada
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Contributions

Contributed substantially to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work or making figures: Alara Altintas, Sidar Copur, Furkan Yavuz, and Mehmet Kanbay Drafted the work or revised it critically for important intellectual content: Mehmet Kanbay, Laura G Sanchez-Lozada, Miguel A. Lanaspa, and Richard J. Johnson.

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Correspondence to Mehmet Kanbay.

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Conflict of Interest

Richard J. Johnson and Miguel A. Lanaspa have equity with Colorado Research Partners LLC that is developing inhibitors of fructose metabolism. Dr Johnson also has stocks with XORTX Therapeutics and has received honoraria from Horizon Pharma. All other authors declare that they have no conflict of interest.

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Kanbay, M., Altıntas, A., Yavuz, F. et al. Responses to Hypoxia: How Fructose Metabolism and Hypoxia-Inducible Factor-1a Pathways Converge in Health and Disease. Curr Nutr Rep 12, 181–190 (2023). https://doi.org/10.1007/s13668-023-00452-5

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