Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-β in murine epidermis

László G. Kömüves, Matthias Schmuth, Ashley J. Fowler, Peter M. Elias, Karen Hanley, Mao Qiang Man, Arthur H. Moser, Jean Marc A Lobaccaro, Mary L. Williams, David J. Mangelsdorf, Kenneth R. Feingold

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)25-34
Number of pages10
JournalJournal of Investigative Dermatology
Volume118
Issue number1
DOIs
StatePublished - 2002

Fingerprint

Epidermis
Liver
Keratinocytes
Skin
Differentiation Antigens
Proliferating Cell Nuclear Antigen
Hyperplasia
Liver X Receptors
Oxysterols
Homeostasis
Retinoid X Receptors
Hairless Mouse
Transglutaminases
Cytoplasmic and Nuclear Receptors
Northern Blotting
Rats
Permeability
Animals
Animal Models
Cells

Keywords

  • Involucrin
  • Keratinocytes
  • Loricrin
  • Permeability barrier
  • Proliferation

ASJC Scopus subject areas

  • Dermatology

Cite this

Kömüves, L. G., Schmuth, M., Fowler, A. J., Elias, P. M., Hanley, K., Man, M. Q., ... Feingold, K. R. (2002). Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-β in murine epidermis. Journal of Investigative Dermatology, 118(1), 25-34. https://doi.org/10.1046/j.0022-202x.2001.01628.x

Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-β in murine epidermis. / Kömüves, László G.; Schmuth, Matthias; Fowler, Ashley J.; Elias, Peter M.; Hanley, Karen; Man, Mao Qiang; Moser, Arthur H.; Lobaccaro, Jean Marc A; Williams, Mary L.; Mangelsdorf, David J.; Feingold, Kenneth R.

In: Journal of Investigative Dermatology, Vol. 118, No. 1, 2002, p. 25-34.

Research output: Contribution to journalArticle

Kömüves, LG, Schmuth, M, Fowler, AJ, Elias, PM, Hanley, K, Man, MQ, Moser, AH, Lobaccaro, JMA, Williams, ML, Mangelsdorf, DJ & Feingold, KR 2002, 'Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-β in murine epidermis', Journal of Investigative Dermatology, vol. 118, no. 1, pp. 25-34. https://doi.org/10.1046/j.0022-202x.2001.01628.x
Kömüves, László G. ; Schmuth, Matthias ; Fowler, Ashley J. ; Elias, Peter M. ; Hanley, Karen ; Man, Mao Qiang ; Moser, Arthur H. ; Lobaccaro, Jean Marc A ; Williams, Mary L. ; Mangelsdorf, David J. ; Feingold, Kenneth R. / Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-β in murine epidermis. In: Journal of Investigative Dermatology. 2002 ; Vol. 118, No. 1. pp. 25-34.
@article{b3f31719e2cb40c5af36594a423aee20,
title = "Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-β in murine epidermis",
abstract = "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.",
keywords = "Involucrin, Keratinocytes, Loricrin, Permeability barrier, Proliferation",
author = "K{\"o}m{\"u}ves, {L{\'a}szl{\'o} G.} and Matthias Schmuth and Fowler, {Ashley J.} and Elias, {Peter M.} and Karen Hanley and Man, {Mao Qiang} and Moser, {Arthur H.} and Lobaccaro, {Jean Marc A} and Williams, {Mary L.} and Mangelsdorf, {David J.} and Feingold, {Kenneth R.}",
year = "2002",
doi = "10.1046/j.0022-202x.2001.01628.x",
language = "English (US)",
volume = "118",
pages = "25--34",
journal = "Journal of Investigative Dermatology",
issn = "0022-202X",
publisher = "Nature Publishing Group",
number = "1",

}

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.

PY - 2002

Y1 - 2002

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

UR - http://www.scopus.com/inward/record.url?scp=0036156083&partnerID=8YFLogxK

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

VL - 118

SP - 25

EP - 34

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 1

ER -