Peroxisome proliferator-activated receptor and farnesoid X receptor ligands differentially regulate sebaceous differentiation in human sebaceous gland organ cultures in vitro

Abstract

Nuclear hormone receptors are important in the regulation of epidermal differentiation and have been implicated in lipid metabolism. In particular, there is evidence suggesting that the activation of peroxisome proliferator-activated receptors (PPARs) is an important factor in the regulation of sebocyte lipogenesis. To determine the role of PPARs, farnesoid X receptor (FXR) and other orphan nuclear hormone receptors in sebaceous gland function in vitro by investigating the biochemical effects of appropriate ligands, and by establishing the RNA and protein expression patterns of a number of nuclear receptors in sebaceous glands ex vivo. Human chest sebaceous glands were maintained in vitro as freshly isolated and as 7-day cultured whole organs. We then studied the effects of appropriate ligands on the glandular rates of lipogenesis and DNA synthesis, as well as determining the mRNA (reverse transcription-polymerase chain reaction) and protein expression patterns (immunohistochemistry/immunoblotting) of the nuclear hormone receptors of interest. PPAR ligands, but not FXR ligands, inhibited sebaceous lipogenesis, in particular the PPARalpha ligands LY 171883 and WY 14643, and the PPARgamma ligands BRL 49653 and 15-deoxy-Delta-12,14-prostaglandin J(2). We detected RNA expression of PPARalpha, PPARbeta, PPARgamma, retinoid X receptor alpha, liver X receptor alpha (LXRalpha) and pregnane X receptor but not FXR in freshly isolated and 7-day maintained sebaceous glands. PPARalpha, PPARbeta, PPARgamma and LXRalpha protein were detected in nuclear extracts of sebaceous glands. We conclude that activation of nuclear hormone receptors, in particular activation of PPARalpha and PPARgamma, can regulate lipogenesis in human sebaceous glands. As suppression of sebum secretion is associated with reduced acne activity, the nuclear hormone receptors involved may open new avenues in the development of novel acne treatments.