Abstract
Cholesterol modification of Hedgehog (Hh) ligands is fundamental for the activity of Hh signaling, and cholesterol biosynthesis is also required for intracellular Hh signaling transduction. Here, we investigated the roles and underlying mechanism of Hh signaling in metabolism of cholesterol. The main components of the Hh pathway are abundantly expressed in both human cytotrophoblasts and trophoblast-like cells. Activation of Hh signaling induces the conversion of cholesterol to progesterone (P4) and estradiol (E2) through up-regulating the expression of steroidogenic enzymes including P450 cholesterol side chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), and aromatase. Moreover, inhibition of Hh signaling attenuates not only Hh-induced expression of steroidogenic enzymes but also the conversion of cholesterol to P4 and E2. Whereas Gli3 is required for Hh-induced P450scc expression, Gli2 mediates the induction of 3β-HSD1 and aromatase. Finally, in ovariectomized nude mice, systemic inhibition of Hh signaling by cyclopamine suppresses circulating P4 and E2 levels derived from a trophoblast-like choricarcinoma xenograft, and attenuates uterine response to P4 and E2. Together these results uncover a hitherto uncharacterized role of Hh signaling in metabolism of cholesterol.
Keywords:
Cholesterol; Hedgehog signaling; Steroids.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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17-Hydroxysteroid Dehydrogenases / genetics
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17-Hydroxysteroid Dehydrogenases / metabolism
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Animals
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Aromatase / genetics
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Aromatase / metabolism
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Cells, Cultured
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Cholesterol / metabolism*
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Estradiol / metabolism*
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Female
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Hedgehog Proteins / metabolism*
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Humans
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Kruppel-Like Transcription Factors / antagonists & inhibitors
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Oncogene Proteins / antagonists & inhibitors
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Progesterone / metabolism*
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RNA, Small Interfering / metabolism
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Signal Transduction / drug effects
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transplantation, Heterologous
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Trophoblasts / cytology
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Trophoblasts / metabolism
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Veratrum Alkaloids / pharmacology
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Zinc Finger Protein GLI1
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Zinc Finger Protein Gli2
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Zinc Finger Protein Gli3
Substances
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GLI3 protein, human
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Gli2 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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Nerve Tissue Proteins
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Oncogene Proteins
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RNA, Small Interfering
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Trans-Activators
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Veratrum Alkaloids
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Zinc Finger Protein GLI1
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Zinc Finger Protein Gli2
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Zinc Finger Protein Gli3
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Progesterone
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Estradiol
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Cholesterol
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17-Hydroxysteroid Dehydrogenases
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3 (or 17)-beta-hydroxysteroid dehydrogenase
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Aromatase
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cyclopamine