Vitamin D Receptor and Coactivators SRC2 and 3 Regulate Epidermis-Specific Sphingolipid Production and Permeability Barrier Formation

Abstract

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.

Vitamin D and the Pathophysiology of Inflammatory Skin Diseases

“…Additionally, 1,25(OH) 2 D regulates the processing of the long-chain glycosylceramides essential for lipid barrier formation. Oda et al [23 ]have shown that VDR knockout mice display a defective permeability barrier due to the reduced production of glucosylceramide and its decreased transport into the lamellar bodies, resulting in a lower lipid content in these bodies. …”

The Role of Vitamin D and its Receptor in Skin and Hair Follicle Biology

“…The expression of components of this complex decrease with differentiation, in association with an increase in Src3 [8]. This latter coactivator is important for the actions of 1,25(OH) 2 D on induction of differentiationspecific markers in keratinocytes and in the synthesis of lipid components of the epidermal barrier [10]. Of note, silencing of Src3 and VDR ablation have similar effects on the lipid barrier, suggesting that this coactivator is essential for the actions of the VDR on lipid barrier formation.…”

“…While this is not accompanied by a gross epidermal defect, the CYP27B1-null mice exhibit an increase in transepidermal water loss and impaired recovery of barrier function following acute barrier disruption. 1,25(OH) 2 D also contributes to barrier function by regulating the synthesis of lipids that play a critical role in permeability barrier formation [10]. The impaired barrier function observed in the VDR-null mice is also associated with a decrease in the synthesis of glucosylceramides and altered barrier lipid composition in vivo.…”

Non-classical effects of vitamin D

“…Эти два сигнальных пути также регулируют продук-цию гликозилцерамидов, входящих в состав липидного барьера кожи, причем зависимо друг от друга, так как нарушение одного из путей не может быть восполнено за счет другого [17][18][19]. Еще одним примером взаимной зависимости этих путей является образование комплек-са Е-кадгерин/катенин, обеспечивающего межклеточную адгезию и участвующего в регуляции дифференцировки кератиноцитов [20].…”