title: Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure.
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.
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, UK.|Department of Biochemistry, University of Cambridge, UK.
authors.forename: Kifayathullah
authors.initials: K
authors.lastname: Liakath-Ali
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Valerie E
authors.identifier: 0000-0003-1547-1975
authors.initials: VE
authors.lastname: Vancollie
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lelliott
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Anneliese O
authors.initials: AO
authors.lastname: Speak
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lafont
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Hayley J
authors.initials: HJ
authors.lastname: Protheroe
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Camilla
authors.initials: C
authors.lastname: Ingvorsen
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: Galli
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Green
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Diane
authors.initials: D
authors.lastname: Gleeson
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Ed
authors.initials: E
authors.lastname: Ryder
authors.affiliation: Centre for Ultrastructural Imaging, King's College London, Guy's Campus, London, UK.
authors.forename: Leanne
authors.initials: L
authors.lastname: Glover
authors.affiliation: Centre for Ultrastructural Imaging, King's College London, Guy's Campus, London, UK.
authors.forename: Gema
authors.initials: G
authors.lastname: Vizcay-Barrena
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Natasha A
authors.initials: NA
authors.lastname: Karp
authors.affiliation: University of Edinburgh Division of Pathology, Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.affiliation: NHS Lothian University Hospitals Trust and University of Edinburgh, Department of Pathology, Western General Hospital, Edinburgh, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brenn
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weyden
mesh_terms: D055574:Alkaline Ceramidase / Q000235:genetics / Q000378:metabolism*; D000505:Alopecia / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D002454:Cell Differentiation; D002518:Ceramides / Q000378:metabolism*; D004734:Energy Metabolism; D004817:Epidermis / Q000002:abnormalities / Q000201:enzymology; D005260:Female; D018859:Hair Follicle / Q000002:abnormalities / Q000201:enzymology; D006706:Homeostasis; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010902:Pituitary Gland / Q000002:abnormalities / Q000201:enzymology; D012627:Sebaceous Glands / Q000002:abnormalities / Q000201:enzymology; D012867:Skin / Q000201:enzymology; D012868:Skin Abnormalities; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D002518:Ceramides; D013107:Sphingolipids; C526753:Acer1 protein, mouse; D055574:Alkaline Ceramidase
keywords: ceramidase; energy homeostasis; sebaceous glands; skin homeostasis