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Liver X Receptor Is a Therapeutic Target for Photoaging and Chronological Skin Aging

Nuclear Receptors and Dermatology (K.C.N.C., Q.S., S.A.J., S.F.J., W.W., Y.W., M.L., M.R.Y., C.C.T., L.P.F., S.N.), Women’s Health and Musculoskeletal Biology, Wyeth Research, Collegeville, Pennsylvania 19426; and Laboratory of Cutaneous Aging Research (I.G.O., J.H.C.), Department of Dermatology, Seoul National University College of Medicine, Seoul National University, Seoul 110-744, Republic of Korea.

Address all correspondence and requests for reprints to: Sunil Nagpal, Nuclear Receptors and Dermatology, Women’s Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426. E-mail: nagpals{at}wyeth.com; or Jin Ho Chung, Laboratory of Cutaneous Aging Research, Department of Dermatology, Seoul National University College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-Gu, Seoul 110-744, Republic of Korea. E-mail: jhchung{at}snu.ac.kr.

Liver X receptors (LXR and -β) are liposensors that exert their metabolic effects by orchestrating the expression of macrophage genes involved in lipid metabolism and inflammation. LXRs are also expressed in other tissues, including skin, where their natural oxysterol ligands induce keratinocyte differentiation and improve epidermal barrier function. To extend the potential use of LXR ligands to dermatological indications, we explored the possibility of using LXR as a target for skin aging. We demonstrate that LXR signaling is down-regulated in cell-based models of photoaging, i.e. UV-activated keratinocytes and TNF-activated dermal fibroblasts. We show that a synthetic LXR ligand inhibits the expression of cytokines and metalloproteinases in these in vitro models, thus indicating its potential in decreasing cutaneous inflammation associated with the etiology of photoaging. Furthermore, a synthetic LXR ligand induces the expression of differentiation markers, ceramide biosynthesis enzymes, and lipid synthesis and transport genes in keratinocytes. Remarkably, LXRβ-null mouse skin showed some of the molecular defects that are observed in chronologically aged human skin. Finally, we demonstrate that a synthetic LXR agonist inhibits UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the ability of an LXR ligand to modulate multiple pathways underlying the etiology of skin aging suggests that LXR is a novel target for developing potential therapeutics for photoaging and chronological skin aging indications.

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRβ  |  LXRα

Ligands:   T0901317

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