Mohamed Antar Aziz Mohamed 2013-11-26

INTRODUCTION

Liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) are ligand activated nuclear receptors that have pivotal roles in lipid metabolism and cholesterol homeostasis through inducting of the expression of involved in lipid metabolism, cholesterol efflux, and transport, such as apolipoprotein E (ApoE) and ATP-binding cassette protein A1 (ABCA1).

LXR α is highly expressed in the liver, whereas LXR β is more ubiquitous. Both isoforms are activated by endogenous oxysterols, such as 22(R)-hydroxycholesterol (22(R)HC) and 24(S)- hydroxycholesterol, and synthetic ligands, such as TO901317 and GW3965.

LXR activators also exhibit potent anti-inflammatory activities in many inflammatory disorders, including dermatitis, atherosclerosis, and pulmonary inflammation, through the suppression of several NF-kB target genes, such as inducible nitric oxide synthase, IL-6, cyclooxygenase 2, matrix metalloproteinase 9, CCL2, CCL7, and IL-1 β.

LXRs are also expressed in the skin tissues such as sebaceous glands, hair follicle, epidermal keratinocytes, and fibroblast.

Topical treatment of LXR activators improves epidermal permeability barrier homeostasis and manifests anti-inflammatory effects in irritant and allergic contact dermatitis models.

Recently, Kumar et al. (2010) demonstrated that LXRs are also expressed in melanocytes. Especially, they showed that LXRs are upregulated in the melanocytes from perilesional skin of vitiligo patients, suggesting that LXRs might be involved in

the regulation of melanin production.

Melanogenesis is the most important function of melanocytes in the skin. Three key melanogenic enzymes, tyrosinase, tyrosinase-related protein-1 (TRP-1), and (TRP-2),

participate in melanogenesis

(MITF) is a master transcription factor for melanogenesis. MITF regulates melanocyte pigmentation, proliferation, and survival.

UV-mediated induction of the proopiomelanocortin (POMC) and MC1 genes that encode the a-melanocyte-stimulating hormone (a-MSH). a-MSH binding to MC1R increases the intracellular levels of cAMP and activates protein kinase A, which subsequently phosphorylates cAMP-responsive element binding (CREB) protein, an activator of MITF gene expression.

On the other hand, activation of extracellular signal–regulated kinase (ERK) induces MITF phosphorylation and degradation, ultimately suppressing melanogenesis.

RESULTS

TO901317-induced LXR activation inhibited melanin synthesis in B16 murine melanoma cells

TO901317 inhibited the expression of melanogenic enzymes and promoted MITF proteolysis

MEK/ERK/RSK signaling pathway is involved in TO901317-induced MITF degradation

The effects of TO901317 (TO) on melanogenesis and the extracellular signal–regulated kinase (ERK) signaling pathway in human melanocytes and MNT-1 cells

TO901317 (TO) reduced UVB-induced hyperpigmentation in brown guinea pig

DISCUSSION

These results suggest that LXRs might be crucial intrinsic factors for the regulation of melanogenesis.