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

doi:10.1038/s41591-018-0003-0

Back

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

Journal article

Peer reviewed

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, …

Nature medicine, Vol.24(5), pp.617-627

05/2018

DOI: 10.1038/s41591-018-0003-0

PMCID: PMC6095711

PMID: 29662201

Files and links (1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/6095711View

Open Access

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.

Keratinocytes - radiation effects

Skin - metabolism

Humans

Stress, Physiological

Homeostasis

Glucose Transporter Type 1 - metabolism

Skin - injuries

Ultraviolet Rays

Psoriasis - pathology

Biological Transport - radiation effects

Gene Deletion

Fatty Acids - metabolism

Skin - pathology

Disease Models, Animal

Psoriasis - therapy

Cell Differentiation - radiation effects

Oxidation-Reduction

Mice, Inbred C57BL

Cells, Cultured

Keratinocytes - pathology

Animals

Glucose Transporter Type 1 - deficiency

Keratinocytes - metabolism

Glucose - metabolism

Cell Proliferation - radiation effects

Details

Title: Subtitle: Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis
Creators: Zhuzhen Zhang - Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, USA
Zhenzhen Zi - Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA
Eunice E Lee - Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, USA
Jiawei Zhao - Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, USA
Diana C Contreras - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Andrew P South - Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA
E Dale Abel - 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
Benjamin F Chong - Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, USA
Travis Vandergriff - Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, USA
Gregory A Hosler - ProPath, Dallas, TX, USA
Philipp E Scherer - Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA
Marcel Mettlen - Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA
Jeffrey C Rathmell - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
Ralph J DeBerardinis - Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA
Richard C Wang - Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, USA. richard.wang@utsouthwestern.edu
Resource Type: Journal article
Publication Details: Nature medicine, Vol.24(5), pp.617-627
DOI: 10.1038/s41591-018-0003-0
PMID: 29662201
PMCID: PMC6095711
NLM abbreviation: Nat Med
ISSN: 1078-8956
eISSN: 1546-170X
Publisher: United States
Grant note: R01 DK105550 / NIDDK NIH HHS K08 CA164047 / NCI NIH HHS K23 AR061441 / NIAMS NIH HHS R01 AR072655 / NIAMS NIH HHS R25 GM062459 / NIGMS NIH HHS R35 CA220449 / NCI NIH HHS
Language: English
Date published: 05/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024539602771

Metrics

41 Record Views

141 Times Cited - Web of Science