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Nat Med. 2018 May;24(5):617-627. doi: 10.1038/s41591-018-0003-0. Epub 2018 Apr 16.

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

Author information

1
Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, USA.
2
Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA.
3
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
4
Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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.
6
ProPath, Dallas, TX, USA.
7
Touchstone Diabetes Center, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
8
Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA.
9
Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, USA.
10
Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA.
11
Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA.
12
Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, USA. richard.wang@utsouthwestern.edu.

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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