TY - JOUR
T1 - Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-β in murine epidermis
AU - Kömüves, László G.
AU - Schmuth, Matthias
AU - Fowler, Ashley J.
AU - Elias, Peter M.
AU - Hanley, Karen
AU - Man, Mao Qiang
AU - Moser, Arthur H.
AU - Lobaccaro, Jean Marc A
AU - Williams, Mary L.
AU - Mangelsdorf, David J.
AU - Feingold, Kenneth R.
N1 - Funding Information:
We thank Timothy Willson (Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC) for his generous gift of 24(S),25-epoxycholesterol. This work was supported by NIH grants HD 29706, AR 29706, and PO 039448, and VA Research Funding. M.S. was supported by a grant from the Austrian Science Fund (Project J2112).
PY - 2002/1
Y1 - 2002/1
N2 - Liver X receptor-α and -β are members of the nuclear hormone receptor superfamily that heterodimerize with retinoid X receptor and are activated by oxysterols. In recent studies we found that treatment of cultured human keratinocytes with oxysterol-stimulated differentiation, as demonstrated by increased expression of involucrin and transglutaminase, and inhibited proliferation. The aims of this study were to determine: (i) whether oxysterols applied topically to the skin of mice induce differentiation in normal epidermis; (ii) whether this effect is mediated via liver X receptor-α and/or liver X receptor-β; and (iii) whether oxysterols normalize epidermal morphology in an animal model of epidermal hyperplasia. Topical treatment of normal hairless mice with 22(R)-hydroxycholesterol or 24(S),25-epoxycholesterol resulted in a decrease in epidermal thickness and a decrease in keratinocyte proliferation assayed by proliferating cell nuclear antigen staining. Moreover, oxysterol treatment increased the levels of involucrin, loricrin, and profilaggrin protein and mRNA in the epidermis, indicating that oxysterols stimulate epidermal differentiation. Additionally, topical oxysterol pretreatment improved permeability barrier homeostasis. Whereas liver X receptor-α-/- mice revealed no alterations in epidermal differentiation, the epidermis was thinner in liver X receptor-β-/- mice than in wild-type mice, with a reduced number of proliferating cell nuclear antigen positive cells and a modest reduction in the expression of differentiation markers. Topical oxysterol treatment induced differentiation in liver X receptor-α-/- mice whereas in liver X receptor-β-/- mice there was no increase in the expression of differentiation markers. Whereas both liver X receptor-α and liver X receptor-β are expressed in cultured human keratinocytes and in fetal rat skin, only liver X receptor-β was observed on northern blotting in adult mouse epidermis. Finally, treatment of hyperproliferative epidermis with oxysterols restored epidermal homeostasis. These studies demonstrate that epidermal differentiation is regulated by liver X receptor-β and that oxysterols, acting via liver X receptor-β, can induce differentiation and inhibit proliferation in vivo. The ability of oxysterols to reverse epidermal hyperplasia suggests that these agents could be beneficial for the treatment of skin disorders associated with hyper-proliferation and/or altered differentiation.
AB - Liver X receptor-α and -β are members of the nuclear hormone receptor superfamily that heterodimerize with retinoid X receptor and are activated by oxysterols. In recent studies we found that treatment of cultured human keratinocytes with oxysterol-stimulated differentiation, as demonstrated by increased expression of involucrin and transglutaminase, and inhibited proliferation. The aims of this study were to determine: (i) whether oxysterols applied topically to the skin of mice induce differentiation in normal epidermis; (ii) whether this effect is mediated via liver X receptor-α and/or liver X receptor-β; and (iii) whether oxysterols normalize epidermal morphology in an animal model of epidermal hyperplasia. Topical treatment of normal hairless mice with 22(R)-hydroxycholesterol or 24(S),25-epoxycholesterol resulted in a decrease in epidermal thickness and a decrease in keratinocyte proliferation assayed by proliferating cell nuclear antigen staining. Moreover, oxysterol treatment increased the levels of involucrin, loricrin, and profilaggrin protein and mRNA in the epidermis, indicating that oxysterols stimulate epidermal differentiation. Additionally, topical oxysterol pretreatment improved permeability barrier homeostasis. Whereas liver X receptor-α-/- mice revealed no alterations in epidermal differentiation, the epidermis was thinner in liver X receptor-β-/- mice than in wild-type mice, with a reduced number of proliferating cell nuclear antigen positive cells and a modest reduction in the expression of differentiation markers. Topical oxysterol treatment induced differentiation in liver X receptor-α-/- mice whereas in liver X receptor-β-/- mice there was no increase in the expression of differentiation markers. Whereas both liver X receptor-α and liver X receptor-β are expressed in cultured human keratinocytes and in fetal rat skin, only liver X receptor-β was observed on northern blotting in adult mouse epidermis. Finally, treatment of hyperproliferative epidermis with oxysterols restored epidermal homeostasis. These studies demonstrate that epidermal differentiation is regulated by liver X receptor-β and that oxysterols, acting via liver X receptor-β, can induce differentiation and inhibit proliferation in vivo. The ability of oxysterols to reverse epidermal hyperplasia suggests that these agents could be beneficial for the treatment of skin disorders associated with hyper-proliferation and/or altered differentiation.
KW - Involucrin
KW - Keratinocytes
KW - Loricrin
KW - Permeability barrier
KW - Proliferation
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UR - http://www.scopus.com/inward/citedby.url?scp=0036156083&partnerID=8YFLogxK
U2 - 10.1046/j.0022-202x.2001.01628.x
DO - 10.1046/j.0022-202x.2001.01628.x
M3 - Article
C2 - 11851872
AN - SCOPUS:0036156083
SN - 0022-202X
VL - 118
SP - 25
EP - 34
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 1
ER -