Alterations in skin and stratified epithelia by constitutively activated PPARα

Peroxisome proliferator-activated receptor (PPAR)α is a pleiotropic regulator in many cell types and has recently been implicated in skin homeostasis. To determine the role of PPARα in skin physiology, transgenic mice were generated using the tetracycline Tet-off regulatory system to target constitutively activated PPARα to the epidermis and other stratified epithelia by the bovine keratin K5 promoter. Expression of the transgene during early development resulted in postnatal lethality within 2 days after birth. A thin epidermis, few hair follicles, and abnormal development of the tongue were observed in neonatal transgenic mice. Early mortality was not observed when transgenic PPARα expression was diminished by administration of doxycycline (dox) to the mothers. The alterations noted in neonatal mice were not observed in adult mice upon re-expression of the PPARα transgene by withdrawing dox. Attenuated hyperplasia of interfollicular epidermis after topical application of the tumor promotor 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was observed in adult mice expressing the PPARα transgene. In addition, expression of the PPARα transgene in mammary gland during pregnancy resulted in abnormal development of this organ and impaired lactation. Further investigations using primary keratinocytes revealed that expression of the transgene in keratinocytes resulted in increased differentiation and decreased proliferation, which may contribute to the observed phenotype in the transgenic mice. Thus, these results indicate that PPARα plays an important role in the development of stratified epithelia including skin, tongue, and mammary gland.