title: The Effect of Small Molecules on Sterol Homeostasis: Measuring 7-Dehydrocholesterol in Dhcr7-Deficient Neuro2a Cells and Human Fibroblasts.
abstract: Well-established cell culture models were combined with new analytical methods to assess the effects of small molecules on the cholesterol biosynthesis pathway. The analytical protocol, which is based on sterol derivation with the dienolphile PTAD, was found to be reliable for the analysis of 7-DHC and desmosterol. The PTAD method was applied to the screening of a small library of pharmacologically active substances, and the effect of compounds on the cholesterol pathway was determined. Of some 727 compounds, over 30 compounds decreased 7-DHC in Dhcr7-deficient Neuro2a cells. The examination of chemical structures of active molecules in the screen grouped the compounds into distinct categories. In addition to statins, our screen found that SERMs, antifungals, and several antipsychotic medications reduced levels of 7-DHC. The activities of selected compounds were verified in human fibroblasts derived from Smith-Lemli-Opitz syndrome (SLOS) patients and linked to specific transformations in the cholesterol biosynthesis pathway.
authors.affiliation: Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University , Nashville, Tennessee 37235, United States.
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Korade
authors.forename: Hye-Young H
authors.initials: HY
authors.lastname: Kim
authors.forename: Keri A
authors.initials: KA
authors.lastname: Tallman
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Genetics, University of Debrecen , Nagyerdei krt. 98, 4032 Debrecen, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Koczok
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Genetics, University of Debrecen , Nagyerdei krt. 98, 4032 Debrecen, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Balogh
authors.forename: Libin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University , Nashville, Tennessee 37235, United States.
authors.forename: Karoly
authors.initials: K
authors.lastname: Mirnics
authors.affiliation: Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University , Nashville, Tennessee 37235, United States.
authors.forename: Ned A
authors.initials: NA
authors.lastname: Porter
mesh_terms: D000818:Animals; D002460:Cell Line; D003684:Dehydrocholesterols / Q000032:analysis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013261:Sterols / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D003684:Dehydrocholesterols; D054852:Small Molecule Libraries; D013261:Sterols; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase