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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 (<jats:italic>Acer1<\/jats:italic>) in the skin. <jats:italic>Acer1<\/jats:italic>\u2010deficient (<jats:italic>Acer1<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that <jats:italic>Acer1<\/jats:italic> is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently <jats:italic>Acer1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice have significant alterations in infundibulum and sebaceous gland architecture. <jats:italic>Acer1<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> skin also shows perturbed hair follicle stem cell compartments. These alterations result in <jats:italic>Acer1<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that <jats:italic>Acer1<\/jats:italic> is indispensable for mammalian skin homeostasis and whole\u2010body energy homeostasis. \u00a9 2016 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.4737","type":"journal-article","created":{"date-parts":[[2016,4,30]],"date-time":"2016-04-30T09:27:41Z","timestamp":1462008461000},"page":"374-383","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole\u2010body energy expenditure"],"prefix":"10.1002","volume":"239","author":[{"given":"Kifayathullah","family":"Liakath\u2010Ali","sequence":"first","affiliation":[{"name":"Centre for Stem Cells and Regenerative Medicine King's College London  UK"},{"name":"Department of Biochemistry 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