Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols

Andrzej T. Slominski; Tae-Kang Kim; Judith V. Hobrath; Zorica Janjetovic; Allen S. W. Oak; Arnold Postlethwaite; Zongtao Lin; Wei Li; Yukimasa Takeda; Anton M. Jetten; Robert C. Tuckey

doi:10.1038/s41598-017-10202-7

Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols

Andrzej T. Slominski (Lead / Corresponding author), Tae-Kang Kim, Judith V. Hobrath, Zorica Janjetovic, Allen S. W. Oak, Arnold Postlethwaite, Zongtao Lin, Wei Li, Yukimasa Takeda, Anton M. Jetten, Robert C. Tuckey

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Abstract

Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non-genomic VDR site. Inhibition of RORα and RORγ transactivation activities in a Tet-on CHO cell reporter system, RORα co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORα and RORγ as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved.

Original language	English
Article number	11434
Pages (from-to)	1-17
Number of pages	17
Journal	Scientific Reports
Volume	7
DOIs	https://doi.org/10.1038/s41598-017-10202-7
Publication status	Published - 12 Sept 2017

Keywords

Endocrinology
Sterols

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Cite this

@article{985508677245438880bf88339c592edc,

title = "Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols",

abstract = "Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non-genomic VDR site. Inhibition of RORα and RORγ transactivation activities in a Tet-on CHO cell reporter system, RORα co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORα and RORγ as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved.",

keywords = "Endocrinology, Sterols",

author = "Slominski, {Andrzej T.} and Tae-Kang Kim and Hobrath, {Judith V.} and Zorica Janjetovic and Oak, {Allen S. W.} and Arnold Postlethwaite and Zongtao Lin and Wei Li and Yukimasa Takeda and Jetten, {Anton M.} and Tuckey, {Robert C.}",

note = "We acknowledge the support by NIH grants R21AR066505, 1R01AR056666 and 1R01AR071189–01A1 to AS; 1R21AR063242, 1S10OD010678, and RR-026377 to WL; VA Program Project Grant IP1BX001607 and VA Clinical Merit Grant I0CX001400 to AP; the University of Western Australia to RCT; and the Intramural Research Program of the NIEHS, NIH (Z01-ES-101586 to AMJ).",

year = "2017",

month = sep,

day = "12",

doi = "10.1038/s41598-017-10202-7",

language = "English",

volume = "7",

pages = "1--17",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Research",

}

TY - JOUR

T1 - Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols

AU - Slominski, Andrzej T.

AU - Kim, Tae-Kang

AU - Hobrath, Judith V.

AU - Janjetovic, Zorica

AU - Oak, Allen S. W.

AU - Postlethwaite, Arnold

AU - Lin, Zongtao

AU - Li, Wei

AU - Takeda, Yukimasa

AU - Jetten, Anton M.

AU - Tuckey, Robert C.

N1 - We acknowledge the support by NIH grants R21AR066505, 1R01AR056666 and 1R01AR071189–01A1 to AS; 1R21AR063242, 1S10OD010678, and RR-026377 to WL; VA Program Project Grant IP1BX001607 and VA Clinical Merit Grant I0CX001400 to AP; the University of Western Australia to RCT; and the Intramural Research Program of the NIEHS, NIH (Z01-ES-101586 to AMJ).

PY - 2017/9/12

Y1 - 2017/9/12

N2 - Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non-genomic VDR site. Inhibition of RORα and RORγ transactivation activities in a Tet-on CHO cell reporter system, RORα co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORα and RORγ as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved.

AB - Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non-genomic VDR site. Inhibition of RORα and RORγ transactivation activities in a Tet-on CHO cell reporter system, RORα co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORα and RORγ as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved.

KW - Endocrinology

KW - Sterols

U2 - 10.1038/s41598-017-10202-7

DO - 10.1038/s41598-017-10202-7

M3 - Article

C2 - 28900196

SN - 2045-2322

VL - 7

SP - 1

EP - 17

JO - Scientific Reports

JF - Scientific Reports

M1 - 11434

ER -

Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols

Abstract

Keywords

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