title: Hedgehog signaling stimulates the conversion of cholesterol to steroids.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Luo
authors.affiliation: The Affiliated Children Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Xiong
authors.affiliation: The Affiliated First Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Ruan
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Jirong
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Affiliated Children Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Chaochun
authors.initials: C
authors.lastname: Zou
authors.affiliation: The Affiliated Children Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Lanfang
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Toxicology, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Iguchi
authors.affiliation: Departments of Orthopaedic Surgery, Medicine and Developmental Biology Washington University in St. Louis, MO, 63110, USA.
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, 310058, China; Departments of Orthopaedic Surgery, Medicine and Developmental Biology Washington University in St. Louis, MO, 63110, USA. Electronic address: xiwu@zju.edu.cn.
authors.forename: Ximei
authors.initials: X
authors.lastname: Wu
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: C065683:GLI3 protein, human; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D011374:Progesterone; D004958:Estradiol; D002784:Cholesterol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D001141:Aromatase; C000541:cyclopamine
keywords: Cholesterol; Hedgehog signaling; Steroids