title: 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, the function of LXRs in melanocytes remains largely unknown. We investigated whether LXR activation would affect melanogenesis. In human primary melanocytes, MNT-1, and B16 melanoma cells, TO901317, a synthetic LXR ligand, inhibited melanogenesis. Small interfering RNA (siRNA) experiments revealed the dominant role of LXRβ in TO901317-mediated antimelanogenesis. Enzymatic activities of tyrosinase were unaffected, but the expression of tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2 was suppressed by TO901317. Expressions of microphthalmia-associated transcription factor (MITF), a master transcriptional regulator of melanogenesis, and cAMP-responsive element-binding activation were not affected. It is noteworthy that the degradation of MITF was accelerated by TO901317. Extracellular signal-regulated kinase (ERK) contributed to TO901317-induced antimelanogenesis, which was evidenced by recovery of melanogenesis with ERK inhibitor. Other LXR ligands, 22(R)-hydroxycholesterol (22(R)HC) and GW3965, also activated ERK and suppressed melanogenesis. The intermediary role of Ras was confirmed in TO901317-induced ERK phosphorylation. Finally, antimelanogenic effects of TO901317 were confirmed in vivo in UVB-tanning model in brown guinea pigs, providing a previously unreported line of evidence that LXRs may be important targets for antimelanogenesis.
authors.affiliation: Amore Pacific R&D Center, Yongin, Republic of Korea.
authors.forename: Chang Seok
authors.initials: CS
authors.lastname: Lee
authors.forename: Miyoung
authors.initials: M
authors.lastname: Park
authors.forename: Jiwon
authors.initials: J
authors.lastname: Han
authors.forename: Ji-Hae
authors.initials: JH
authors.lastname: Lee
authors.forename: Il-Hong
authors.initials: IH
authors.lastname: Bae
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Choi
authors.forename: Eui Dong
authors.initials: ED
authors.lastname: Son
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Park
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D017495:Hyperpigmentation / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000071518:Liver X Receptors; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism*; D008545:Melanoma; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D012878:Skin Neoplasms; D012880:Skin Pigmentation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D013449:Sulfonamides / Q000494:pharmacology; D014466:Ultraviolet Rays; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D013449:Sulfonamides; C497234:MITF protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides