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

Mi Hee Shin, Yuri Lee, Min Kyoung Kim, Dong Hun Lee, Jin Ho Chung

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number105449
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume195
DOIs
StatePublished - 1 Dec 2019

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Calcitriol
Matrix Metalloproteinases
Vitamin D
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Keratinocytes
Skin
Cholesterol
Irradiation
Ketoconazole
Mixed Function Oxygenases
Up-Regulation
Enzymes
Skin Aging
Messenger RNA
7-dehydrocholesterol
Human Body
Small Interfering RNA
Down-Regulation
Aging of materials
Availability

Keywords

  • 1α,25-dihydroxyvitamin D
  • 7-dehydrocholesterol
  • 7-dehydrocholesterol reductase
  • Cholesterol
  • CYP27B1
  • MMP-1
  • UV

Cite this

@article{c726e5d556dd4149b080f6198e07fa26,
title = "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",
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.",
keywords = "1α,25-dihydroxyvitamin D, 7-dehydrocholesterol, 7-dehydrocholesterol reductase, Cholesterol, CYP27B1, MMP-1, UV",
author = "Shin, {Mi Hee} and Yuri Lee and Kim, {Min Kyoung} and Lee, {Dong Hun} and Chung, {Jin Ho}",
year = "2019",
month = "12",
day = "1",
doi = "10.1016/j.jsbmb.2019.105449",
language = "English",
volume = "195",
journal = "Journal of Steroid Biochemistry and Molecular Biology",
issn = "0960-0760",
publisher = "Elsevier Ltd",

}

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

PY - 2019/12/1

Y1 - 2019/12/1

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.

AB - 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.

KW - 1α,25-dihydroxyvitamin D

KW - 7-dehydrocholesterol

KW - 7-dehydrocholesterol reductase

KW - Cholesterol

KW - CYP27B1

KW - MMP-1

KW - UV

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U2 - 10.1016/j.jsbmb.2019.105449

DO - 10.1016/j.jsbmb.2019.105449

M3 - Article

C2 - 31470109

AN - SCOPUS:85071865717

VL - 195

JO - Journal of Steroid Biochemistry and Molecular Biology

JF - Journal of Steroid Biochemistry and Molecular Biology

SN - 0960-0760

M1 - 105449

ER -