KERATINOCYTE DIFFERENTIATION IS STIMULATED BY ACTIVATORS OF THE NUCLEAR HORMONE-RECEPTOR PPAR-ALPHA

Peroxisome proliferator activated receptors (PPAR) belong to the super family of nuclear hormone receptors that heterodimerize with the retin oid X receptor and regulate transcription of several genes involved in lipid metabolism and adipocyte differentiation. Because of the role o f 1,25-dihydroxyvitamin D-3 and retinoic acid working through similar receptors (the vitamin D receptor and retinoic acid receptor, respecti vely) on keratinocyte differentiation, we have examined the effects of activators of PPAR alpha on keratinocyte differentiation. The fate of cornified envelope formation was increased 3-fold in keratinocytes ma intained in low calcium (0.03 mM) and incubated in the presence of clo fibric acid, a potent PPAR alpha activator. Involucrin, a cornified en velope precursor, and the cross-linking enzyme transglutaminase, were increased at both the message level (2-7-fold) and the protein level ( 4-12-fold) by clofibric acid. Furthermore, physiologic doses of the fa tty acids oleic acid, linoleic acid, and eicosatetraynoic acid, which are also activators of PPAR alpha, also induced involucrin and transgl utaminase protein and mRNA. In contrast, the PPAR gamma ligand prostag landin 52 had no effect on protein or mRNA levels of involucrin or tra nsglutaminase. Levels of involucrin and transglutaminase mRNA and prot ein were induced by clofibric acid in keratinocytes incubated in 1.2 m M calcium, a concentration which by itself induces keratinocyte differ entiation. Finally, PPAR alpha activators inhibit DNA synthesis. This study demonstrates that PPAR alpha activators, including putative endo genous ligands such as fatty acids, induce differentiation and inhibit proliferation in keratinocytes, and suggests a regulatory role for th e PPAR alpha in epidermal homeostasis.