1. ¹Department of Dermatology, University of California and VA Medical Center, San Francisco, California, USA
2. ²Department of Medicine, University of California and VA Medical Center, San Francisco, California, USA

Correspondence: Dr Kenneth R. Feingold, University of California and VA Medical Center, Metabolism Section (111F), 4150 Clement Street, San Francisco, California 94121, USA. E-mail: kfngld@itsa.ucsf.edu

Received 14 April 2005; Revised 30 August 2005; Accepted 17 September 2005; Published online 22 December 2005.

Abstract

Previously, we demonstrated that topical applications of peroxisome proliferator-activated receptors (PPARs) and liver X receptor (LXR) activators improve permeability barrier homeostasis. We showed further that stimulation of epidermal differentiation provides one mechanism that could account for such improvement. Here, we studied the effects of these agents on the lipid matrix of the stratum corneum. Hairless mice were treated topically with activators of PPAR (WY14643), PPAR (GW1514), PPAR (ciglitazone), and LXR (22(R)-cholesterol or TO901317) or vehicle twice daily for 3 days. All activators significantly increased epidermal cholesterol, fatty acid, and sphingolipid synthesis, including the production of barrier-specific ceramide species. In addition, lamellar body (LB) formation, secretion, and post-secretory processing accelerated significantly following acute barrier disruption in PPAR/LXR-activator-treated animals. Finally, the activity of epidermal -glucocerebrosidase, a key lipid-processing enzyme, increased in PPAR/LXR-activator-treated animals. Thus, topical PPAR and LXR activators stimulate epidermal lipid synthesis, increase LB secretion, and accelerate extracellular lipid processing, providing additional mechanisms that further account for their ability to improve epidermal permeability barrier homeostasis. Since the liposensors are activated by endogenous lipid metabolites, they may serve as unique regulators of barrier homeostasis.