Abstract
The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1‐deficient (Acer1−/−) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1 −/− mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1−/− skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1−/− mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole‐body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
The skin functions as a barrier that protects the body from the external environment and controls water and heat loss
The increased ceramide levels were visualized by immunostaining with an anti-ceramide antibody, which showed strong staining within the stratum corneum (Figure 1H), and there was a significantly increased number of apoptotic cells in the skin of alkaline ceramidase 1 (Acer1)−/− mice relative to wild-type (Figure 1I)
Previous in vitro studies have reported that ACER1 fails to hydrolyse any dihydroceramides or phytoceramides [5], further investigations would be needed to determine whether the increase in levels of these lipids observed in the skin of Acer1−/− mice is a direct result of lack of ACER1-mediated hydrolysis or some indirect/compensatory effect
Summary
The skin functions as a barrier that protects the body from the external environment and controls water and heat loss. Barrier function is established through the multistage differentiation of keratinocytes in the epidermis, in which keratinocytes differentiate from proliferative cells in the basal layer into cornified cells in the stratum corneum. Ceramide is the main sphingolipid component of the stratum corneum, which is comprised of terminally differentiated corneocytes with characteristic multilamellar membrane unit structures that mediate barrier function [1]. Altered expression of ceramides has been identified in human skin conditions such as psoriasis and atopic dermatitis [2,3]. Seven ceramidases have been identified, categorized by their pH optima: acid ceramidase (ASAH1), neutral ceramidase (ASAH2, ASAH2B, ASAH2C) and alkaline ceramidases 1–3 (ACER1–3)
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