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

Zhuzhen Zhang, Zhenzhen Zi, Eunice E. Lee, Jiawei Zhao, Diana C. Contreras, Andrew P. South, E. Dale Abel, Benjamin F. Chong, Travis Vandergriff, Gregory A. Hosler, Philipp E. Scherer, Marcel Mettlen, Jeffrey C. Rathmell, Ralph J. DeBerardinis, Richard C. Wang

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalNature Medicine
DOIs
StateAccepted/In press - Apr 16 2018

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Keratinocytes
Psoriasis
Skin
Homeostasis
Glucose
Wounds and Injuries
Therapeutics
Organoids
Inflammation
Sphingolipids
Physiological Stress
Oxidative stress
Hexoses
Pathology
Ablation
Metabolism
Hyperplasia
Oxidative Stress
Nucleotides
Genes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis. / Zhang, Zhuzhen; Zi, Zhenzhen; Lee, Eunice E.; Zhao, Jiawei; Contreras, Diana C.; South, Andrew P.; Abel, E. Dale; Chong, Benjamin F.; Vandergriff, Travis; Hosler, Gregory A.; Scherer, Philipp E.; Mettlen, Marcel; Rathmell, Jeffrey C.; DeBerardinis, Ralph J.; Wang, Richard C.

In: Nature Medicine, 16.04.2018, p. 1-11.

Research output: Contribution to journalArticle

Zhang, Zhuzhen ; Zi, Zhenzhen ; Lee, Eunice E. ; Zhao, Jiawei ; Contreras, Diana C. ; South, Andrew P. ; Abel, E. Dale ; Chong, Benjamin F. ; Vandergriff, Travis ; Hosler, Gregory A. ; Scherer, Philipp E. ; Mettlen, Marcel ; Rathmell, Jeffrey C. ; DeBerardinis, Ralph J. ; Wang, Richard C. / Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis. In: Nature Medicine. 2018 ; pp. 1-11.
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