Ligands for nuclear receptors such as the peroxisomal proliferator activated receptor have been shown to improve epidermal differentiation, increasing ceramide and filaggrin levels (122). This superfamily of nuclear transcription receptors includes the retinoic acid receptors, the steroid receptors, the thyroid receptors, and the vitamin D receptors and also the peroxisome proliferator activated receptor (PPAR), together with farnesol activated receptor (FXR) and the liver activated receptor (LXR). These transcription factors bind their respective ligands and regulate many of the aspects of cellular proliferation and differentiation. Fatty acids are important ligands for the PPAR receptor, farnesol for the FXR, and hydroxylated cholesterol derivatives or cholestenoic acid for the LXR. All of these pathways stimulated epidermal differentiation and increased the synthesis of involucrin, filaggrin, and enzymes of the ceramide synthesis pathway.
The transcription factor most intensively investigated is the PPAR. There are three main PPAR isoforms: alpha, beta/delta, and gamma. Nevertheless, PPAR delta was recently observed to be the predominant PPAR subtype in human keratinocytes, whereas PPAR alpha and gamma were only induced during epidermal differentiation, suggesting non-redundant functions during differentiation (123). Respective ligands for all of these isoforms increased epidermal differentiation. Pharmaceutical ligands for the PPAR receptors increase ceramide synthesis in vitro by increasing the expression of SPT, glucosyl ceramide synthase, and glucocerebrosidase but not sphingomyelinase (124). More recently PPAR delta ligands were found to be the most potent in inducing epidermal differentiation (tetrathioacetic acid) by increasing involucrin and transglutaminase while decreasing proliferation.
Petroselinic acid (125) and conjugated linoleic acid (126) have been identified as potent PPAR alpha activators improving epidermal differentiation, reducing inflammation, increasing extracellular matrix components, and eliciting skin lightening. In vitro increased levels of transglutaminase, involucrin, filaggrin, and CE formation were observed in keratinocytes after treatment with petroselinic acid. These effects were confirmed in vivo by short-term patch testing studies over three weeks and increases in involucrin and filaggrin were also observed. Using this technology, improvements in the signs of photodamage, skin tone and dry skin were observed in a 12-week clinical study on forearm skin (127). Octadecenedioic acid has also recently been identified as a pan-PPAR agonist (with a preference for PPAR gamma) and has been shown to reduce skin hyperpigmentation, but with its PPAR agonist activities it is also expected to improve epidermal differentiation (128).