Vitamin D receptor and coactivators SRC2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation.
The vitamin D receptor (VDR) is a nuclear hormone receptor that controls transcription of target genes. It exerts its biological effects through transcriptional coactivators. Previously, we identified two distinct classes of VDR coactivators, VDR-interacting protein (DRIP) and steroid receptor coactivator (SRC) at different stages of keratinocyte differentiation. Here, we determined the functions of VDR and coactivators in lipid production and permeability barrier formation. Silencing of either VDR, SRC2, or SRC3 resulted in decreases in specific glucosylceramide (GlcCer) species but not other lipids such as cholesterol and free fatty acids. Their silencing also caused decreased transcription of fatty acid elongase and ceramide glucosyltransferase, which are critical for the synthesis of epidermis-unique GlcCer species, and defects in lamellar body formation associated with decreased expression of the lipid transporter ATP-binding cassette transporter protein 12. VDR null mice exhibit abnormal barrier function with altered lipid composition in vivo. These results demonstrate that VDR and coactivators SRC2 and SRC3, which are also involved in other nuclear receptors as well, are critical for epidermis-specific sphingolipid production and barrier formation. In contrast, DRIP silencing had no apparent effect on these processes indicating that the two classes of coactivators are differentially utilized.
Oda
Yuko
Y
Department of Medicine, University of California, San Francisco, California, USA. yuko.oda@ucsf.edu
Uchida
Yoshikazu
Y
Moradian
Sam
S
Crumrine
Debra
D
Elias
Peter M
PM
Bikle
Daniel D
DD
D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005963:Glucosylceramides / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3; D010539:Permeability; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*
D005230:Fatty Acids, Nonesterified; D005963:Glucosylceramides; D008055:Lipids; D051958:Nuclear Receptor Coactivator 2; D018167:Receptors, Calcitriol; D013107:Sphingolipids; D015534:Trans-Activators; D002784:Cholesterol; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3