Abstract
The nuclear hormone receptor PPARβ/δ is integral to efficient wound re-epithelialization and implicated in epidermal maturation. However, the mechanism underlying the latter process of epidermal differentiation remains unclear. We showed that ligand-activated PPARβ/δ indirectly stimulated keratinocyte differentiation, requiring de novo gene transcription and protein translation. Using organotypic skin cultures constructed from PPARβ/δ- and angiopoietin-like 4 (ANGPTL4)-knockdown human keratinocytes, we showed that the expression of ANGPTL4, a PPARβ/δ target gene, is essential for the receptor mediated epidermal differentiation. The pro-differentiation effect of PPARβ/δ agonist GW501516 was also abolished when keratinocytes were co-treated with PPARβ/δ antagonist GSK0660 and similarly in organotypic skin culture incubated with blocking ANGPTL4 monoclonal antibody targeted against the C-terminal fibrinogen-like domain. Our focused real-time PCR gene expression analysis comparing the skin biopsies from wildtype and ANGPTL4-knockout mice confirmed a consistent down-regulation of numerous genes involved in epidermal differentiation and proliferation in the ANGPTL4-knockout skin. We further showed that the deficiency of ANGPTL4 in human keratinocytes and mice skin have diminished expression of various protein kinase C isotypes and phosphorylated transcriptional factor activator protein-1, which are well-established for their roles in keratinocyte differentiation. Chromatin immunoprecipitation confirmed that ANGPTL4 stimulated the activation and binding of JUNB and c-JUN to the promoter region of human involucrin and transglutaminase type 1 genes, respectively. Taken together, we showed that PPARβ/δ regulates epidermal maturation via ANGPTL4-mediated signalling pathway.
Highlights
Adult epidermis is a stratified self-renewing epithelium in which keratinocytes in the basal and suprabasal layers cease to divide, concomitant with their outward movement, giving rise to differentiated cell layers of the spinous layer, granular layer and the stratum corneum
We showed that PPARb/d-mediated upregulation of angiopoietin-like 4 (ANGPTL4) expression in human keratinocytes stimulates the expression of protein kinase C (PKC) and activities of activator protein-1 (AP-1) transcription factors to modulate epidermal differentiation
We provide a mechanism for the role of ANGPTL4, PPARb/d target gene, in epidermal differentiation via AP-1-dependent signaling pathways
Summary
Adult epidermis is a stratified self-renewing epithelium in which keratinocytes in the basal and suprabasal layers cease to divide, concomitant with their outward movement, giving rise to differentiated cell layers of the spinous layer, granular layer and the stratum corneum. A tightly regulated homeostatic balance of epidermal cell proliferation and differentiation ensures proper epidermal structure and function [1,2]. Transcriptional regulation plays an important role in skin maturation and abundant information is available on the various differentiation markers expressed in the epidermis [2,3]. One of the largest known classes of transcription factors, have been implicated in skin development and maturation. Glucocorticoid, estrogen, vitamin D and retinoid X receptors, among others, were reported to either accelerate the maturation of the skin permeability barrier or modulate the differentiation of the epidermis [4,5]. PPARb/d is an important regulator of keratinocyte survival in the wounded epidermis and is involved in cell adhesion and migration [11,12]. A novel homeostatic control of keratinocyte proliferation was recently found, whereby PPARb/
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