title: Basis for improved permeability barrier homeostasis induced by PPAR and LXR activators: liposensors stimulate lipid synthesis, lamellar body secretion, and post-secretory lipid processing.
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 PPARalpha (WY14643), PPARdelta (GW1514), PPARgamma (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 beta-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.
authors.affiliation: Department of Dermatology, University of California and VA Medical Center, San Francisco, California 94121, USA.
authors.forename: Mao-Qiang
authors.initials: MQ
authors.lastname: Man
authors.forename: Eung-Ho
authors.initials: EH
authors.lastname: Choi
authors.forename: Matt
authors.initials: M
authors.lastname: Schmuth
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uchida
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Walter M
authors.initials: WM
authors.lastname: Holleran
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000819:agonists*; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D006706:Homeostasis; D050356:Lipid Metabolism / Q000187:drug effects*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D057093:Orphan Nuclear Receptors; D010539:Permeability; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*
chemical_list: D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D020025:Peroxisome Proliferators; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol