Liver X receptor activation inhibits melanogenesis through the acceleration of ERK-mediated MiTF degradation

Abstract

Liver X receptors(LXRs) are nuclear receptors that act as ligand-activated transcription factors regulating lipid metabolism and inflammation. In the skin, activation of LXRs stimulates differentiation of keratinocytes and augments lipid synthesis in sebocytes. However, function of LXRs in melanocytes has not been elucidated. Here we investigated if LXR activation might affect melanogenesis, the representative function of melanocytes. In human primary melanocytes and B16 melanoma cells, TO901317, a synthetic LXR ligand inhibited melanin synthesis. Enzymatic activities of tyrosinase were unaffected but the expression of melanogenesis-related proteins such as tyrosinase, tyrosinase related protein(TRP)-1 and -2 was suppressed by TO901317. Expression of microphthalmia-associated transcription factor(MiTF), a master transcriptional regulator of melanogenesis, and upstream event, cAMP responsive element-binding activation were not affected. Of note, the degradation of MiTF was substantially accelerated by TO901317. Extracellular signal-regulated kinase(ERK) contributed to TO901317-induced anti-melanogenesis, which was supported by recovery of melanogenesis with an ERK inhibitor. Other LXR ligands like 22(R)-hydroxycholesterol and GW3965 also activated ERK and suppressed melanogenesis. Anti-melanogenic effects of TO901317 were confirmed in vivo in UVB-tanning model in brownish guinea pigs where topical application of TO901317 significantly reduced UVB-induced hyper-pigmentation, providing the first line of evidence that LXRs may be a novel target for anti-melanogenesis. JSID AbstractsJournal of Dermatological ScienceVol. 69Issue 2Preview Full-Text PDF