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Abstract

Proliferating cells, compared with quiescent cells, are more dependent on glucose for their growth. Although glucose transport in keratinocytes is mediated largely by the Glut1 facilitative transporter, we found that keratinocyte-specific ablation of Glut1 did not compromise mouse skin development and homeostasis. Ex vivo metabolic profiling revealed altered sphingolipid, hexose, amino acid, and nucleotide metabolism in Glut1-deficient keratinocytes, thus suggesting metabolic adaptation. However, cultured Glut1-deficient keratinocytes displayed metabolic and oxidative stress and impaired proliferation. Similarly, Glut1 deficiency impaired in vivo keratinocyte proliferation and migration within wounded or UV-damaged mouse skin. Notably, both genetic and pharmacological Glut1 inactivation decreased hyperplasia in mouse models of psoriasis-like disease. Topical application of a Glut1 inhibitor also decreased inflammation in these models. Glut1 inhibition decreased the expression of pathology-associated genes in human psoriatic skin organoids. Thus, Glut1 is selectively required for injury- and inflammation-associated keratinocyte proliferation, and its inhibition offers a novel treatment strategy for psoriasis.

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Acknowledgements

We thank the R. Gordillo for help with lipidomic studies; C. Yang, J. Sudderth, L. Zacharias, and J. Galvan Resendiz and the Children’s Research Institute Metabolomics Facility for help with metabolomic studies; L.-C. Tseng for help with patient sample collection; and P. Gerami for help with psoriasis models. This work was supported by the following grants: NCI R35 CA220449-01 and the Welch Foundation (I-1733-06) to R.J.D.; NIAMS K23AR061441 to B.F.C.; NIDDK DK10550 to J.C.R.; and NIAMS 1R01AR072655, Burroughs Wellcome Fund CAMS (1010978), and American Cancer Society/Simmons Cancer Center (ACS-IRG-02-196) to R.C.W.

Author information

Author notes

  1. These authors contributed equally: Zhenzhen Zi and Eunice E. Lee.

Affiliations

  1. Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, USA

    • Zhuzhen Zhang
    • , Eunice E. Lee
    • , Jiawei Zhao
    • , Benjamin F. Chong
    • , Travis Vandergriff
    • , Gregory A. Hosler
    •  & Richard C. Wang
  2. Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA

    • Zhenzhen Zi
  3. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    • Diana C. Contreras
    •  & Jeffrey C. Rathmell
  4. Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA

    • Andrew P. South
  5. Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    • E. Dale Abel
  6. ProPath, Dallas, TX, USA

    • Gregory A. Hosler
  7. Touchstone Diabetes Center, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    • Philipp E. Scherer
  8. Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA

    • Philipp E. Scherer
    •  & Marcel Mettlen
  9. Children’s Medical Center Research Institute, UT Southwestern Medical Center, Dallas, USA

    • Ralph J. DeBerardinis
  10. Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA

    • Ralph J. DeBerardinis
  11. Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA

    • Ralph J. DeBerardinis

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Contributions

Z. Zhang, R.J.D., and R.C.W. designed the experiments. Z. Zhang, E.E.L., J.Z., M.M., and R.C.W. performed experiments. E.D.A. provided Glut1fl/fl mice. A.P.S. provided SCCT8 squamous cell carcinoma cells. B.F.C. enrolled patients. Z. Zhang, Z. Zi, E.E.L., J.Z., D.C.C., M.M., G.A.H., T.V., J.C.R., P.E.S., R.J.D., and R.C.W. analyzed data; R.C.W. and Z. Zhang wrote the manuscript, to which all authors contributed.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Richard C. Wang.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–11 and Supplementary Table 1

  2. Reporting Summary

  3. Supplementary Dataset 1

    Lipidomics

  4. Supplementary Dataset 2

    Combined metabolomics

  5. Supplementary Video 1

    WT keratinocyte scratch assay video

  6. Supplementary Video 2

    K14.Glut1 keratinocyte scratch assay video

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DOI

https://doi.org/10.1038/s41591-018-0003-0