title: What dictates the accumulation of desmosterol in the developing brain?
abstract: The brain is the most cholesterol-enriched tissue in the body. During brain development, desmosterol, an immediate precursor of cholesterol, transiently accumulates up to 30% of total brain sterols. This massive desmosterol deposition appears to be present in all mammalian species reported so far, including humans, but how it is achieved is not well understood. Here, we propose that desmosterol accumulation in the developing brain may be primarily caused by post-transcriptional repression of 3β-hydroxysterol 24-reductase (DHCR24) by progesterone. Furthermore, distinct properties of desmosterol may serve to increase the membrane active pool of sterols in the brain: desmosterol cannot be hydroxylated to generate 24S-hydroxycholesterol, a brain derived secretory sterol, desmosterol has a reduced propensity to be esterified as compared to cholesterol, and desmosterol may activate LXR to stimulate astrocyte sterol secretion. This regulated accumulation of desmosterol by progesterone-induced suppression of DHCR24 may facilitate the rapid enrichment and distribution of membrane sterols in the developing brain.
authors.affiliation: Institute of Biomedicine, Anatomy, University of Helsinki, Helsinki, Finland.
authors.forename: Maurice
authors.initials: M
authors.lastname: Jansen
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Dario
authors.initials: D
authors.lastname: Greco
authors.forename: Gian Carlo
authors.initials: GC
authors.lastname: Bellenchi
authors.forename: Umberto
authors.initials: U
authors.lastname: di Porzio
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brown
authors.forename: Elina
authors.initials: E
authors.lastname: Ikonen
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D001923:Brain Chemistry / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D003897:Desmosterol / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000096:biosynthesis; D011374:Progesterone / Q000378:metabolism
chemical_list: D000071518:Liver X Receptors; D009419:Nerve Tissue Proteins; D057093:Orphan Nuclear Receptors; D003897:Desmosterol; D011374:Progesterone; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499056:Dhcr24 protein, mouse