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.

A novel adamantyl benzylbenzamide derivative, AP736, suppresses melanogenesis through the inhibition of cAMP‐PKA‐CREB‐activated microphthalmia‐associated transcription factor and tyrosinase expression

“…MiTF receives increasing interests as an ideal antimelanogenic target as it can modulate the survival and melanogenesis of melanocytes (17)(18)(19). Inhibition of MiTF transcription by AP736 was mediated by the blockade of cAMP-PKA-CREB activation.…”

Liver X receptor activation induces apoptosis of melanoma cell through caspase pathway

“…For example, LXRs could induce lipid synthesis in sebocytes, and inhibit the expressions of cytokines and metalloproteinases in skin-photoaging models [16-18]. LXRs are upregulated in melanocytes from perilesional skin of vitiligo patients [19], and LXR activation could inhibit the melanogenesis in human primary melanocytes and murine B16 melanoma cells by downregulating melanogenic enzymes through Ras- and ERK-induced MITF degradation [20]. Our study presented LXRs as key target proteins for the treatment of melanoma, which does not conflict others’ finding, depending on the use of different agonist and dosages.…”

Stimulating effect of modified Goa-Gi-Um herbal remedy on melanogenesis in B16F10 melanoma cells

“…Roh 등은 멜라닌 합성시에 tyrosinase을 안정화시키고 melanosome 구조를 유지할 수 있도록 도와주는 것이 TRP-1이고 이것은 효소 기능도 있어 dihydroxyindole carboxylic acid oxidase 로서 DHICA를 indol-5,6-quinone-2-carboxylic acid로 산화시켜 tyrosinase의 downstream에서 멜라닌을 생성하는 데 중요한 역할을 한다 5,6) . 일부 연구에서는 멜라닌 합성 정도 는 tyrosinase의 발현과 활성에 의해서 조절되지만, TRP-1과 TRP-2의 발현과는 관련이 없다는 보고도 있지만 11,19) , 본 연 구처럼 멜라닌의 합성은 TRP-1과 TRP-2의 발현과 관련이 있다는 연구도 있다 20) . …”