title: Topical liver x receptor activators accelerate postnatal acidification of stratum corneum and improve function in the neonate.
abstract: In neonatal rat stratum corneum (SC), pH declines from pH 6.8 at birth to adult levels (pH 5.0-5.5) over 5-6 d. Liver X receptor (LXR) activators stimulate keratinocyte differentiation, improve permeability barrier homeostasis, and accelerate the in utero development of the SC. In this manuscript we determined the effect of LXR activators on SC acidification in the neonatal period and whether these activators correct the functional abnormalities in permeability barrier homeostasis and SC integrity/cohesion. Formation of the acid SC-buffer system was accelerated by topically applying the LXR activator, 22(R)-hydroxycholesterol, and non-oxysterol activators of LXR, TO-901317, and GW-3965. A sterol which does not activate LXR had no effect. LXR activation increased secretory phospholipase A(2) (sPLA(2)) activity and conversely, inhibition of sPLA(2) activity prevented the LXR induced increase in SC acidification, suggesting that increasing sPLA(2) accounts in part, for the LXR stimulation of acidification. LXR activation resulted in an improvement in permeability barrier homeostasis, associated with an increased maturation of lamellar membranes attributable to an increased beta-glucocerebrosidase activity. SC integrity cohesion also normalized in LXR-activator-treated animals and was associated with an increase in corneodesmosomes and in desmoglein 1 expression. These results demonstrate that LXR activators stimulate the formation of an acidic SC and improve both permeability barrier homeostasis and SC integrity/cohesion.
authors.affiliation: Dermatology and Medical Service, Veterans Affairs Medical Center, San Francisco, California, USA. fluhr@derma.uni-jena.de
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Fluhr
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Man
authors.initials: M
authors.lastname: Mao-Qiang
authors.forename: David G
authors.initials: DG
authors.lastname: Moskowitz
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D027682:Cation Transport Proteins / Q000378:metabolism; D002784:Cholesterol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D051183:Desmoglein 1 / Q000378:metabolism; D005260:Female; D005962:Glucosylceramidase / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D000071518:Liver X Receptors; D008565:Membrane Proteins / Q000378:metabolism; D023421:Models, Animal; D057093:Orphan Nuclear Receptors; D010741:Phospholipases A / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D012867:Skin / Q000196:embryology* / Q000254:growth & development* / Q000648:ultrastructure; D012879:Skin Physiological Phenomena; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D051183:Desmoglein 1; D000071518:Liver X Receptors; D008565:Membrane Proteins; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D002784:Cholesterol; D010741:Phospholipases A; D005962:Glucosylceramidase