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

Nature Medicine volume 24, pages 617–627 (2018)Cite this article

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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References

  1. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  Google Scholar 

  2. Palm, W. et al. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162, 259–270 (2015).

    Article  CAS  Google Scholar 

  3. Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591–1602 (2014).

    Article  CAS  Google Scholar 

  4. Hensley, C. T. et al. Metabolic heterogeneity in human lung tumors. Cell 164, 681–694 (2016).

    Article  CAS  Google Scholar 

  5. Faubert, B. et al. Lactate metabolism in human lung tumors. Cell 171, 358–371.e359 (2017).

    Article  CAS  Google Scholar 

  6. Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).

    Article  Google Scholar 

  7. Michalek, R. D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011).

    Article  CAS  Google Scholar 

  8. Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).

    Article  CAS  Google Scholar 

  9. De Bock, K. et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154, 651–663 (2013).

    Article  Google Scholar 

  10. Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192–197 (2015).

    Article  CAS  Google Scholar 

  11. Thorens, B. & Mueckler, M. Glucose transporters in the 21st Century. Am. J. Physiol. Endocrinol. Metab. 298, E141–E145 (2010).

    Article  CAS  Google Scholar 

  12. Cura, A. J. & Carruthers, A. Role of monosaccharide transport proteins in carbohydrate assimilation, distribution, metabolism, and homeostasis. Compr. Physiol. 2, 863–914 (2012).

    PubMed  PubMed Central  Google Scholar 

  13. Gherzi, R. et al. “HepG2/erythroid/brain” type glucose transporter (GLUT1) is highly expressed in human epidermis: keratinocyte differentiation affects GLUT1 levels in reconstituted epidermis. J. Cell. Physiol. 150, 463–474 (1992).

    Article  CAS  Google Scholar 

  14. Elson, D. A., Ryan, H. E., Snow, J. W., Johnson, R. & Arbeit, J. M. Coordinate up-regulation of hypoxia inducible factor (HIF)-1α and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res. 60, 6189–6195 (2000).

    CAS  PubMed  Google Scholar 

  15. Tao, J. et al. Expression of GLUT-1 in psoriasis and the relationship between GLUT-1 upregulation induced by hypoxia and proliferation of keratinocyte growth. J. Dermatol. Sci. 51, 203–207 (2008).

    Article  CAS  Google Scholar 

  16. Tochio, T., Tanaka, H. & Nakata, S. Glucose transporter member 1 is involved in UVB-induced epidermal hyperplasia by enhancing proliferation in epidermal keratinocytes. Int. J. Dermatol. 52, 300–308 (2013).

    Article  CAS  Google Scholar 

  17. Watt, S. A. et al. Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma. Oncogene 30, 4666–4677 (2011).

    Article  CAS  Google Scholar 

  18. Young, C. D. et al. Modulation of glucose transporter 1 (GLUT1) expression levels alters mouse mammary tumor cell growth in vitro and in vivo. PLoS One 6, e23205 (2011).

    Article  CAS  Google Scholar 

  19. Wellberg, E. A. et al. The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis. Breast Cancer Res. 18, 131 (2016).

    Article  Google Scholar 

  20. Macintyre, A. N. et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61–72 (2014).

    Article  CAS  Google Scholar 

  21. Liu, Y. et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol. Cancer Ther. 11, 1672–1682 (2012).

    Article  CAS  Google Scholar 

  22. Kuehne, A. et al. Acute activation of oxidative pentose phosphate pathway as first-line response to oxidative stress in human skin cells. Mol. Cell 59, 359–371 (2015).

    Article  CAS  Google Scholar 

  23. Zhang, Z. Z. et al. Glutathione depletion, pentose phosphate pathway activation, and hemolysis in erythrocytes protecting cancer cells from vitamin C-induced oxidative stress. J. Biol. Chem. 291, 22861–22867 (2016).

    Article  CAS  Google Scholar 

  24. Schäfer, M. & Werner, S. Nrf2: a regulator of keratinocyte redox signaling. Free Radic. Biol. Med. 88, 243–252 (2015).

    Article  Google Scholar 

  25. Amen, N. et al. Differentiation of epidermal keratinocytes is dependent on glucosylceramide:ceramide processing. Hum. Mol. Genet. 22, 4164–4179 (2013).

    Article  CAS  Google Scholar 

  26. Jennemann, R. et al. Integrity and barrier function of the epidermis critically depend on glucosylceramide synthesis. J. Biol. Chem. 282, 3083–3094 (2007).

    Article  CAS  Google Scholar 

  27. Takashima, A. & Bergstresser, P. R. Impact of UVB radiation on the epidermal cytokine network. Photochem. Photobiol. 63, 397–400 (1996).

    Article  CAS  Google Scholar 

  28. Raja, S., Sivamani, K., Garcia, M. S. & Isseroff, R. R. Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front. Biosci. 12, 2849–2868 (2007).

    Article  CAS  Google Scholar 

  29. Hawkes, J. E., Gudjonsson, J. E. & Ward, N. L. The snowballing literature on imiquimod-induced skin inflammation in mice: a critical appraisal. J. Invest. Dermatol. 137, 546–549 (2017).

    Article  CAS  Google Scholar 

  30. van der Fits, L. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182, 5836–5845 (2009).

    Article  Google Scholar 

  31. Chan, J. R. et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J. Exp. Med. 203, 2577–2587 (2006).

    Article  CAS  Google Scholar 

  32. Flutter, B. & Nestle, F. O. TLRs to cytokines: mechanistic insights from the imiquimod mouse model of psoriasis. Eur. J. Immunol. 43, 3138–3146 (2013).

    Article  CAS  Google Scholar 

  33. Tortola, L. et al. Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J. Clin. Invest. 122, 3965–3976 (2012).

    Article  CAS  Google Scholar 

  34. Van Belle, A. B. et al. IL-22 is required for imiquimod-induced psoriasiform skin inflammation in mice. J. Immunol. 188, 462–469 (2012).

    Article  Google Scholar 

  35. Sa, S. M. et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J. Immunol. 178, 2229–2240 (2007).

    Article  CAS  Google Scholar 

  36. Fuchs, E. Scratching the surface of skin development. Nature 445, 834–842 (2007).

    Article  CAS  Google Scholar 

  37. Freinkel, R. K. Metabolism of glucose-C-14 by human skin in vitro. J. Invest. Dermatol. 34, 37–42 (1960).

    Article  CAS  Google Scholar 

  38. Sparks, J. W., Avery, G. B., Fletcher, A. B., Simmons, M. A. & Glinsmann, W. H. Parenteral galactose therapy in the glucose-intolerant premature infant. J. Pediatr. 100, 255–259 (1982).

    Article  CAS  Google Scholar 

  39. Barone, S. et al. Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension. J. Biol. Chem. 284, 5056–5066 (2009).

    Article  CAS  Google Scholar 

  40. Zhao, F. Q. & Keating, A. F. Functional properties and genomics of glucose transporters. Curr. Genomics 8, 113–128 (2007).

    Article  CAS  Google Scholar 

  41. Holden, H. M., Rayment, I. & Thoden, J. B. Structure and function of enzymes of the Leloir pathway for galactose metabolism. J. Biol. Chem. 278, 43885–43888 (2003).

    Article  CAS  Google Scholar 

  42. Cantor, J. R. et al. Physiologic medium rewires cellular metabolism and reveals uric acid as an endogenous inhibitor of UMP synthase. Cell 169, 258–272.e217 (2017).

    Article  CAS  Google Scholar 

  43. Hamanaka, R. B. et al. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci. Signal. 6, ra8 (2013).

    Article  Google Scholar 

  44. Farber, S. & Diamond, L. K. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N. Engl. J. Med. 238, 787–793 (1948).

    Article  CAS  Google Scholar 

  45. Heidelberger, C. et al. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 179, 663–666 (1957).

    Article  CAS  Google Scholar 

  46. Eugui, E. M., Almquist, S. J., Muller, C. D. & Allison, A. C. Lymphocyte-selective cytostatic and immunosuppressive effects of mycophenolic acid in vitro: role of deoxyguanosine nucleotide depletion. Scand. J. Immunol. 33, 161–173 (1991).

    Article  CAS  Google Scholar 

  47. Greb, J. E. et al. Psoriasis. Nat. Rev. Dis. Primers 2, 16082 (2016).

    Article  Google Scholar 

  48. Mehta, N. N. et al. Systemic and vascular inflammation in patients with moderate to severe psoriasis as measured by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT): a pilot study. Arch. Dermatol. 147, 1031–1039 (2011).

    Article  CAS  Google Scholar 

  49. Kamleh, M. A. et al. LC-MS metabolomics of psoriasis patients reveals disease severity-dependent increases in circulating amino acids that are ameliorated by anti-TNFα treatment. J. Proteome Res. 14, 557–566 (2015).

    Article  CAS  Google Scholar 

  50. Kang, H. et al. Exploration of candidate biomarkers for human psoriasis based on gas chromatography-mass spectrometry serum metabolomics. Br. J. Dermatol. 176, 713–722 (2017).

    Article  CAS  Google Scholar 

  51. Checa, A. et al. Circulating levels of sphingosine-1-phosphate are elevated in severe, but not mild psoriasis and are unresponsive to anti-TNF-α treatment. Sci. Rep. 5, 12017 (2015).

    Article  CAS  Google Scholar 

  52. Lee, E. E. et al. A protein kinase C phosphorylation motif in GLUT1 affects glucose transport and is mutated in GLUT1 deficiency syndrome. Mol. Cell 58, 845–853 (2015).

    Article  CAS  Google Scholar 

  53. Telang, S. et al. Small molecule inhibition of 6-phosphofructo-2-kinase suppresses t cell activation. J. Transl. Med. 10, 95 (2012).

    Article  CAS  Google Scholar 

  54. Koo, S. W., Hirakawa, S., Fujii, S., Kawasumi, M. & Nghiem, P. Protection from photodamage by topical application of caffeine after ultraviolet irradiation. Br. J. Dermatol. 156, 957–964 (2007).

    Article  CAS  Google Scholar 

  55. Wang, X., Ge, J., Tredget, E. E. & Wu, Y. The mouse excisional wound splinting model, including applications for stem cell transplantation. Nat. Protoc. 8, 302–309 (2013).

    Article  CAS  Google Scholar 

  56. Lichti, U., Anders, J. & Yuspa, S. H. Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat. Protoc. 3, 799–810 (2008).

    Article  CAS  Google Scholar 

  57. Holland, W. L. et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 17, 790–797 (2013).

    Article  CAS  Google Scholar 

  58. Carles, J. Colorimetric microdetermination of phosphorus. Bull. Soc. Chim. Biol. (Paris) 38, 255–257 (1956).

    CAS  Google Scholar 

  59. Mullen, A. R. et al. Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep. 7, 1679–1690 (2014).

    Article  CAS  Google Scholar 

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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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Author notes

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

Authors and 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.

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Correspondence to Richard C. Wang.

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Supplementary information

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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