Glut1 – A target for Psoriasis treatment

Psoriasis is a common autoimmune skin condition cause by increased turnover of skin cells resulting in inflammation and build‑up of itchy, flaky skin. There is no cure for psoriasis with topical treatments, immunosuppressants and phototherapy currently used to control the symptoms.

Proliferating cells often prefer glucose as an easy supply of energy and its availability is regulated by the Glut transporters. There are 13 Glut proteins expressed in different tissues and in response to certain stimuli depending upon the function of the tissues. Glut1 is most commonly expressed, including in keratinocytes where expression is increased during wound healing and UV‑induced hyperplasia. Glut1 expression has also been demonstrated in psoriatic plaques and Wang et al., have investigated the role of glucose metabolism in psoriasis.

Glut1 is the only substantially expressed glucose transporter in keratinocytes, so its depletion largely abolishes glucose transport in those cells. Glut1 depleted keratinocytes also displayed defects in proliferation in vitro.

Microarray analysis identified pathways contributing to the impaired proliferation under glucose deficiency belonged to family of genes related to cell‑cycle progression and cell division. Also transcripts related to redox homeostasis were among the genes with the most elevated expression in keratinocytes from Glut1 knockout mice compared to wild type (WT) mice.

Consistent with this, the Glut1 knock out mice showed impairment in wound closure rates and delayed recovery after UV‑B irradiation suggesting that glucose uptake is an efficient response to physiologically relevant stressors.

However, despite the evidence of metabolism and oxidative stress caused by loss of glucose transport in Glut1 depleted keratinocytes, Glut1 knock out mice showed normal epidermal development.

Ex vivo metabolic profiling revealed different profiles for the epidermis from Glut1 knockout and WT mice, which suggested metabolic adaptation to loss of glucose uptake. Transcriptional and metabolomics analysis revealed that changes in amino acid, fatty acid and sugars such as galactose and fructose might have help to maintain the biosynthetic cycles, rescuing proliferating defects in Glut1 deficient keratinocytes in vivo.

Mouse models of psoriasiform hyperplasia (induced through either topical application of imiquimod or intra dermal injection of IL‑23) showed that skin treated with imiquimod displayed upregulated Glut1 expression.

In addition when psoriatic plaques were treated with the topical GLUT inhibitor WZB117, decreased scaling and significantly inhibited skin thickening was observed when compared to WT. In contrast, in Glut1 knockout mice, the epidermis was protected from imiquimod-induced psoriasiform hyperplasia.

Glut1 expression was increased in psoriatic plaques in humans and metabolomic analysis revealed elevated serum levels of some amino acids in patients with psoriasis

In conclusion the authors suggested that glucose uptake was required for proliferating keratinocytes, but not for normal skin development and function, and that inhibition of glucose transport may be a promising therapy for certain skin diseases such as psoriasis which stem from keratinocytes over-proliferation. The authors further speculated that the topical application of glucose transport inhibitors may be beneficial in other cell types in the skin, including infiltrating lymphocytes, and thereby limit inflammation in vivo. In summary the study provided insight into keratinocyte adaptation to survive in the absence of glucose metabolism and identified the glucose transporter, Glut1, as a potential target for the treatment of hyper proliferative psoriasis.

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Epistem's Oncology and Imaging Models

At Epistem we can offer a range of in vivo skin models including mouse models of psoriasis induced by imiquimod and a humanized skin graft model (Dependent on tissue availability). For in vitro studies we offer growth studies in primary monolayer cultures, ex vivo culture of skin and a living skin equivalent culture for test compound screening.

All our models are supported by GCLP compliant histology/IHC and genomic analytical services. We have in-house bioinformatics support for all of our gene expression studies and have extensive experience identifying biomarkers or biomarker signatures in a variety of tissues including skin.

“Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis”. Zhuzhen Zang et al (2018) Nature Medicine, e-access

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