ACTIVATORS OF THE NUCLEAR HORMONE RECEPTORS PPAR-ALPHA AND FXR ACCELERATE THE DEVELOPMENT OF THE FETAL EPIDERMAL PERMEABILITY BARRIER

Members of the superfamily of nuclear hormone receptors which are obli gate heterodimeric partners of the retinoid X receptor may be importan t in epidermal development. Here, we examined the effects of activator s of the receptors for vitamin D-3 and retinoids, and of the peroxisom e proliferator activated receptors (PPARs) and the farnesoid X-activat ed receptor (FXR), on the development of the fetal epidermal barrier i n vitro. Skin explants from gestational day 17 rats (term is 22 d) are unstratified and Lack a Stratum corneum (SC). After incubation in hor mone-free media for 3-4 d, a multilayered SC replete with mature lamel lar membranes in the interstices and a functionally Competent barrier appear. 9-cis or all-trans retinoic acid, 1,25 dihydroxyvitamin D-3, o r the PPAR gamma Ligands prostaglandin J(2) or troglitazone did not af fect the development of barrier function or epidermal morphology. In c ontrast, activators of the PPAR alpha, oleic acid, linoleic acid, and clofibrate, accelerated epidermal development, resulting in mature lam ellar membranes, a multilayered SC, and a competent barrier after 2 d of incubation. The FXR activators, all-trans farnesol and juvenile hor mone III, also accelerated epidermal barrier development. Activities o f beta-glucocerebrosidase and steroid sulfatase, enzymes previously li nked to barrier maturation, also increased after treatment with PPAR a lpha and FXR activators. In contrast, isoprenoids, such as nerolidol, cis-farnesol, or geranylgeraniol, or metabolites in the cholesterol pa thway, such as meyalonate, squalene, or 25-hydroxycholesterol, did not alter barrier development, Finally, additive effects were observed in explants incubated with clofibrate and farnesol together in suboptima l concentrations which alone did not affect barrier development. These data indicate a putative physiologic role for PPAR alpha and FXR in e pidermal barrier development.