UV increases skin-derived 1α,25-dihydroxyvitamin D 3 production, leading to MMP-1 expression by altering the balance of vitamin D and cholesterol synthesis from 7-dehydrocholesterol

• Published in: The Journal of steroid biochemistry and molecular biology 2019-12, Vol.195, p.105449
• Main Authors: Shin, Mi Hee, Lee, Yuri, Kim, Min-Kyoung, Lee, Dong Hun, Chung, Jin Ho
• Format: Article
• Language: English
• Subjects: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - genetics; Adult; Cells, Cultured; Dehydrocholesterols - metabolism; Humans; Keratinocytes - metabolism; Keratinocytes - radiation effects; Matrix Metalloproteinase 1 - metabolism; Middle Aged; Skin - metabolism; Skin - radiation effects; Ultraviolet Rays; Vitamin D - analogs & derivatives; Vitamin D - metabolism; Vitamins - metabolism
• ISSN: 1879-1220
• DOI: 10.1016/j.jsbmb.2019.105449

The skin is a unique site in the human body that has the capacity to synthesize the active form of vitamin D, 1α,25-dihydroxyvitamin D (1α,25(OH) D ), from 7-dehydrocholesterol (7DHC) upon UV irradiation. Keratinocytes express both 25-hydroxylase (CYP27A1 and CYP2R1) and 1α-hydroxylase (CYP27B1), critical enzymes involved in active vitamin D synthesis. Here, we investigated the effect of skin-derived 1α,25(OH) D , synthesized purely within the keratinocytes, on MMP-1 expression. Treatment of human epidermal keratinocytes with 1α,25(OH) D but not 7DHC or 25OHD , significantly increased MMP-1 expression. UV irradiation increases 1α,25(OH) D levels, and ketoconazole inhibits UV-induced production of 1α,25(OH) D . Upregulation of MMP-1 by UV was reversed by inhibition of 1α,25(OH) D synthesis using ketoconazole or CYP27B1 siRNA. In keratinocytes, 7DHC is a substrate for both cholesterol and 1α,25(OH) D synthesis. We demonstrated that UV irradiation leads to decreased expression of DHCR7 (7-dehydrocholesterol reductase), the enzyme that converts 7DHC to cholesterol. Inhibition of DHCR7 with its inhibitor BM15766 decreased cholesterol synthesis and increased UV-induced MMP-1 expression, which was attenuated by ketoconazole. These findings suggest that UV-induced reduction of DHCR7 leads to a decrease in cholesterol synthesis, thereby increasing 7DHC availability for 1α,25(OH) D production, which enhances MMP-1 expression. Finally, UV irradiation in human skin in vivo significantly increased CYP27B1 mRNA and decreased DHCR7 mRNA expression. Taken together, we demonstrate here that skin-derived 1α,25(OH) D significantly increases MMP-1 expression in human keratinocytes, a previously unappreciated function of 1α,25(OH) D Moreover, UV irradiation upregulates the enzyme CYP27B1, which leads to 1α,25(OH) D synthesis, but downregulates the cholesterol-producing enzyme DHCR7, both of which collectively lead to increased MMP-1 expression in human keratinocytes. This pathway may be exploited to develop a novel cutaneous anti-aging agent that blocks local cutaneous 1α,25(OH) D synthesis.