title: Oxysterols inhibit differentiation and fusion of term primary trophoblasts by activating liver X receptors.
abstract: Oxygenated cholesterol metabolites known as oxysterols display potent biological activities ranging from regulation of lipid homeostasis to cytotoxicity. Oxysterols have previously been shown to inhibit the invasion of first trimester trophoblasts, an effect which involves activation of the nuclear liver X receptors (LXRs). In the present study, we investigated the effects of several oxysterols on syncytialisation (differentiation and fusion) in term placental trophoblasts. Treatment of cultured term primary trophoblast cells with oxysterols [25-hydroxycholesterol, 7-ketocholesterol, 22(R)-hydroxycholesterol] and the synthetic LXR agonist T0901317 at non-toxic doses decreased expression of GCM-1 and HERV-W mRNA and reduced hCG secretion and placental alkaline phosphatase activity, indicative of diminished trophoblast differentiation. Furthermore, treatment with these compounds also decreased cell fusion measured by E-cadherin immunostaining and quantification of syncytialised nuclei. Treatment with an LXR antagonist (geranylgeranyl diphosphate) abrogated the inhibitory effects of oxysterols and T0901317 on trophoblast syncytialisation indicating that these effects are mediated by LXR. These findings suggest that oxysterols impair differentiation and fusion of term trophoblast cells via an LXR-dependent mechanism.
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, King Edward Memorial Hospital, 374 Bagot Rd, Subiaco, Perth, WA 6008, Australia.
authors.forename: I L M H
authors.initials: IL
authors.lastname: Aye
authors.forename: B J
authors.initials: BJ
authors.lastname: Waddell
authors.forename: P J
authors.initials: PJ
authors.lastname: Mark
authors.forename: J A
authors.initials: JA
authors.lastname: Keelan
mesh_terms: D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002459:Cell Fusion; D006063:Chorionic Gonadotropin / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins; D005260:Female; D015686:Gene Products, env / Q000096:biosynthesis; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007653:Ketocholesterols / Q000494:pharmacology*; D000071518:Liver X Receptors; D009687:Nuclear Proteins / Q000096:biosynthesis; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis; D014327:Trophoblasts / Q000187:drug effects* / Q000502:physiology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000469:Alkaline Phosphatase; D006063:Chorionic Gonadotropin; D004268:DNA-Binding Proteins; D015686:Gene Products, env; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D000071518:Liver X Receptors; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D013449:Sulfonamides; D014157:Transcription Factors; C491089:GCM1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C405335:syncytin; C003585:22-hydroxycholesterol; C007997:25-hydroxycholesterol; C003001:7-ketocholesterol