Activators of PPARs and LXR decrease the adverse effects of exogenous glucocorticoids on the epidermis

Marianne Demerjian, Eung Ho Choi, Mao Qiang Man, Sandra Chang, Peter M. Elias, Kenneth R. Feingold

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

While glucocorticoids (GC) exert beneficial effects (anti-inflammatory), they also have adverse effects on the epidermis including decreased epidermal differentiation, decreased keratinocyte proliferation, and decreased cutaneous permeability barrier homeostasis. Thus, the purpose of this study was to develop strategies to prevent these GC toxicities using simultaneous topical treatments in clobetasol-treated mice. While a triple-lipid mixture of stratum corneum lipids (ceramide, free fatty acid and cholesterol) was previously shown to reverse the GC-induced abnormality in cutaneous barrier function [J Invest Dermatol, 120 (2003) 456], this lipid mixture did not prevent the GC-induced abnormalities in either keratinocyte proliferation or differentiation. As activators of PPARα, β/δ, γ and LXR, regulate keratinocyte proliferation and differentiation and improve permeability barrier homeostasis, we next assessed the effects of these activators during concurrent GC treatment. Co-application of either ciglitazone (PPARγ activator), clofibrate (PPARα activator) or 22R (OH) cholesterol (LXR activator) with clobetasol prevented the decrease in involucrin, filaggrin and loricrin expression. By contrast, a PPARβ/ δ activator (GW501516) normalized only the expression of involucrin and filaggrin but not loricrin. Moreover, topical application of PPARα, β/δ or LXR activators partially prevented the decrease in keratinocyte proliferation in GC-treated murine skin, as measured using PCNA, while no effect was seen after co-treatment with PPARγ activators. Finally, PPARγ and PPARβ/δ activators but not PPARα and LXR activators improved permeability barrier homeostasis in GC-treated mice. Together, these studies demonstrate that PPAR and LXR activators can prevent several of the adverse effects of topical GC on the epidermis.

Original languageEnglish
Pages (from-to)643-649
Number of pages7
JournalExperimental Dermatology
Volume18
Issue number7
DOIs
Publication statusPublished - 2009 Jun 17

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Peroxisome Proliferator-Activated Receptors
Epidermis
Glucocorticoids
Keratinocytes
Clobetasol
Permeability
Homeostasis
Lipids
Skin
Cholesterol
Clofibrate
Ceramides
Proliferating Cell Nuclear Antigen
Nonesterified Fatty Acids
Cornea
Toxicity
Anti-Inflammatory Agents

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology

Cite this

Demerjian, Marianne ; Choi, Eung Ho ; Man, Mao Qiang ; Chang, Sandra ; Elias, Peter M. ; Feingold, Kenneth R. / Activators of PPARs and LXR decrease the adverse effects of exogenous glucocorticoids on the epidermis. In: Experimental Dermatology. 2009 ; Vol. 18, No. 7. pp. 643-649.
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abstract = "While glucocorticoids (GC) exert beneficial effects (anti-inflammatory), they also have adverse effects on the epidermis including decreased epidermal differentiation, decreased keratinocyte proliferation, and decreased cutaneous permeability barrier homeostasis. Thus, the purpose of this study was to develop strategies to prevent these GC toxicities using simultaneous topical treatments in clobetasol-treated mice. While a triple-lipid mixture of stratum corneum lipids (ceramide, free fatty acid and cholesterol) was previously shown to reverse the GC-induced abnormality in cutaneous barrier function [J Invest Dermatol, 120 (2003) 456], this lipid mixture did not prevent the GC-induced abnormalities in either keratinocyte proliferation or differentiation. As activators of PPARα, β/δ, γ and LXR, regulate keratinocyte proliferation and differentiation and improve permeability barrier homeostasis, we next assessed the effects of these activators during concurrent GC treatment. Co-application of either ciglitazone (PPARγ activator), clofibrate (PPARα activator) or 22R (OH) cholesterol (LXR activator) with clobetasol prevented the decrease in involucrin, filaggrin and loricrin expression. By contrast, a PPARβ/ δ activator (GW501516) normalized only the expression of involucrin and filaggrin but not loricrin. Moreover, topical application of PPARα, β/δ or LXR activators partially prevented the decrease in keratinocyte proliferation in GC-treated murine skin, as measured using PCNA, while no effect was seen after co-treatment with PPARγ activators. Finally, PPARγ and PPARβ/δ activators but not PPARα and LXR activators improved permeability barrier homeostasis in GC-treated mice. Together, these studies demonstrate that PPAR and LXR activators can prevent several of the adverse effects of topical GC on the epidermis.",
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Activators of PPARs and LXR decrease the adverse effects of exogenous glucocorticoids on the epidermis. / Demerjian, Marianne; Choi, Eung Ho; Man, Mao Qiang; Chang, Sandra; Elias, Peter M.; Feingold, Kenneth R.

In: Experimental Dermatology, Vol. 18, No. 7, 17.06.2009, p. 643-649.

Research output: Contribution to journalArticle

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