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.

• Authors: 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
• Journal: Nature medicine (Nat Med) Vol. 24 Issue 5 Pg. 617-627 (05 2018) ISSN: 1546-170X [Electronic] United States
• PMID: 29662201 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• Glucose Transporter Type 1
• Glucose

Topics

• Animals
• Biological Transport (radiation effects)
• Cell Differentiation (radiation effects)
• Cell Proliferation (radiation effects)
• Cells, Cultured
• Disease Models, Animal
• Fatty Acids (metabolism)
• Gene Deletion
• Glucose (metabolism)
• Glucose Transporter Type 1 (deficiency, metabolism)
• Homeostasis
• Humans
• Keratinocytes (metabolism, pathology, radiation effects)
• Mice, Inbred C57BL
• Oxidation-Reduction
• Psoriasis (pathology, therapy)
• Skin (injuries, metabolism, pathology)
• Stress, Physiological
• Ultraviolet Rays