Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis

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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Fig. 1: Primary keratinocytes showed impaired proliferation after Glut1 deletion.
Fig. 2: Glut1 is required for proliferation and redox homeostasis in primary keratinocytes.
Fig. 3: Glut1 is dispensable for normal epidermal development and differentiation, and its deletion induces metabolic reprogramming.
Fig. 4: Alternative hexoses and fatty acids partially rescue Glut1 deficiency in keratinocytes.
Fig. 5: Glut1 is required for proliferation in response to UV-B irradiation and wounding.
Fig. 6: Genetic or topical inhibition of glucose transport decreases psoriasiform hyperplasia.

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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.

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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.

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Correspondence to Richard C. Wang.

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Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Table 1

Reporting Summary

Supplementary Dataset 1

Lipidomics

Supplementary Dataset 2

Combined metabolomics

Supplementary Video 1

WT keratinocyte scratch assay video

Supplementary Video 2

K14.Glut1 keratinocyte scratch assay video

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Zhang, Z., Zi, Z., Lee, E.E. et al. Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis. Nat Med 24, 617–627 (2018). https://doi.org/10.1038/s41591-018-0003-0

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