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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 languageEnglish (US)
Article number11434
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Ergosterol
Keratinocytes
Skin
CHO Cells
Adrenal Glands
Epidermis
Transcriptional Activation
Agar
Melanoma
Swine
Gene Expression
Serum
Research

All Science Journal Classification (ASJC) codes

  • General

Cite this

Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols. / Slominski, Andrzej T.; Kim, Tae Kang; Hobrath, Judith V.; Janjetovic, Zorica; Oak, Allen S.W.; Postlethwaite, Arnold; Lin, Zongtao; Li, Wei; Takeda, Yukimasa; Jetten, Anton M.; Tuckey, Robert C.

In: Scientific reports, Vol. 7, No. 1, 11434, 01.12.2017.

Research output: Contribution to journalArticle

Slominski, AT, Kim, TK, Hobrath, JV, Janjetovic, Z, Oak, ASW, Postlethwaite, A, Lin, Z, Li, W, Takeda, Y, Jetten, AM & Tuckey, RC 2017, 'Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols', Scientific reports, vol. 7, no. 1, 11434. https://doi.org/10.1038/s41598-017-10202-7
Slominski, Andrzej T. ; Kim, Tae Kang ; Hobrath, Judith V. ; Janjetovic, Zorica ; Oak, Allen S.W. ; Postlethwaite, Arnold ; Lin, Zongtao ; Li, Wei ; Takeda, Yukimasa ; Jetten, Anton M. ; Tuckey, Robert C. / Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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