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UV increases skin-derived 1α,25-dihydroxyvitamin D3 production, leading to MMP-1 expression by altering the balance of vitamin D and cholesterol synthesis from 7-dehydrocholesterol.
J Steroid Biochem Mol Biol. 2019 12; 195:105449.JS

Abstract

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 D3 (1α,25(OH)2D3), 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)2D3, synthesized purely within the keratinocytes, on MMP-1 expression. Treatment of human epidermal keratinocytes with 1α,25(OH)2D3, but not 7DHC or 25OHD3, significantly increased MMP-1 expression. UV irradiation increases 1α,25(OH)2D3 levels, and ketoconazole inhibits UV-induced production of 1α,25(OH)2D3. Upregulation of MMP-1 by UV was reversed by inhibition of 1α,25(OH)2D3 synthesis using ketoconazole or CYP27B1 siRNA. In keratinocytes, 7DHC is a substrate for both cholesterol and 1α,25(OH)2D3 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)2D3 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)2D3 significantly increases MMP-1 expression in human keratinocytes, a previously unappreciated function of 1α,25(OH)2D3. Moreover, UV irradiation upregulates the enzyme CYP27B1, which leads to 1α,25(OH)2D3 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)2D3 synthesis.

Authors+Show Affiliations

Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea; Institute on Aging, Seoul National University, Seoul, Republic of Korea. Electronic address: jhchung@snu.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31470109

Citation

Shin, Mi Hee, et al. "UV Increases Skin-derived 1α,25-dihydroxyvitamin D3 Production, Leading to MMP-1 Expression By Altering the Balance of Vitamin D and Cholesterol Synthesis From 7-dehydrocholesterol." The Journal of Steroid Biochemistry and Molecular Biology, vol. 195, 2019, p. 105449.
Shin MH, Lee Y, Kim MK, et al. UV increases skin-derived 1α,25-dihydroxyvitamin D3 production, leading to MMP-1 expression by altering the balance of vitamin D and cholesterol synthesis from 7-dehydrocholesterol. J Steroid Biochem Mol Biol. 2019;195:105449.
Shin, M. H., Lee, Y., Kim, M. K., Lee, D. H., & Chung, J. H. (2019). UV increases skin-derived 1α,25-dihydroxyvitamin D3 production, leading to MMP-1 expression by altering the balance of vitamin D and cholesterol synthesis from 7-dehydrocholesterol. The Journal of Steroid Biochemistry and Molecular Biology, 195, 105449. https://doi.org/10.1016/j.jsbmb.2019.105449
Shin MH, et al. UV Increases Skin-derived 1α,25-dihydroxyvitamin D3 Production, Leading to MMP-1 Expression By Altering the Balance of Vitamin D and Cholesterol Synthesis From 7-dehydrocholesterol. J Steroid Biochem Mol Biol. 2019;195:105449. PubMed PMID: 31470109.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - UV increases skin-derived 1α,25-dihydroxyvitamin D3 production, leading to MMP-1 expression by altering the balance of vitamin D and cholesterol synthesis from 7-dehydrocholesterol. AU - Shin,Mi Hee, AU - Lee,Yuri, AU - Kim,Min-Kyoung, AU - Lee,Dong Hun, AU - Chung,Jin Ho, Y1 - 2019/08/27/ PY - 2019/04/19/received PY - 2019/08/02/revised PY - 2019/08/17/accepted PY - 2019/8/31/pubmed PY - 2020/1/15/medline PY - 2019/8/31/entrez KW - 1α,25-dihydroxyvitamin D(3) KW - 7-dehydrocholesterol KW - 7-dehydrocholesterol reductase KW - CYP27B1 KW - Cholesterol KW - MMP-1 KW - UV SP - 105449 EP - 105449 JF - The Journal of steroid biochemistry and molecular biology JO - J Steroid Biochem Mol Biol VL - 195 N2 - 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 D3 (1α,25(OH)2D3), 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)2D3, synthesized purely within the keratinocytes, on MMP-1 expression. Treatment of human epidermal keratinocytes with 1α,25(OH)2D3, but not 7DHC or 25OHD3, significantly increased MMP-1 expression. UV irradiation increases 1α,25(OH)2D3 levels, and ketoconazole inhibits UV-induced production of 1α,25(OH)2D3. Upregulation of MMP-1 by UV was reversed by inhibition of 1α,25(OH)2D3 synthesis using ketoconazole or CYP27B1 siRNA. In keratinocytes, 7DHC is a substrate for both cholesterol and 1α,25(OH)2D3 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)2D3 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)2D3 significantly increases MMP-1 expression in human keratinocytes, a previously unappreciated function of 1α,25(OH)2D3. Moreover, UV irradiation upregulates the enzyme CYP27B1, which leads to 1α,25(OH)2D3 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)2D3 synthesis. SN - 1879-1220 UR - https://www.unboundmedicine.com/medline/citation/31470109/UV_increases_skin_derived_1α25_dihydroxyvitamin_D3_production_leading_to_MMP_1_expression_by_altering_the_balance_of_vitamin_D_and_cholesterol_synthesis_from_7_dehydrocholesterol_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-0760(19)30227-4 DB - PRIME DP - Unbound Medicine ER -