title: LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins.
abstract: Lipid trafficking in the brain is essential for the maintenance and repair of neuronal membranes, especially after neurotoxic insults. However, brain lipid metabolism is not completely understood. In plasma, LCAT catalyses the esterification of free cholesterol on circulating lipoproteins, a key step in the maturation of HDL. Brain lipoproteins are apolipoprotein E (apoE)-containing, HDL-like particles secreted initially as lipid-poor discs by glial cells. LCAT is synthesized within the brain, suggesting that it may play a key role in the maturation of these lipoproteins. Here we demonstrate that astrocytes are the primary producers of brain LCAT. This LCAT esterifies free cholesterol on nascent apoE-containing lipopoproteins secreted from glia. ApoE is the major LCAT activator in glia-conditioned media (GCM), and both the cholesterol transporter ABCA1 and apoE are required to generate glial LCAT substrate particles. LCAT deficiency leads to the appearance of abnormal approximately 8 nm particles in GCM, and exogenous LCAT restores the lipoprotein particle distribution to the wild-type (WT) pattern. In vivo, complete LCAT deficiency results in a dramatic increase in apoE-HDL and reduced apolipoprotein A-I (apoA-I)-HDL in murine cerebrospinal fluid (CSF). These data show that brain LCAT esterifies cholesterol on glial-derived apoE-lipoproteins, and influences CSF apoE and apoA-I levels.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Veronica
authors.initials: V
authors.lastname: Hirsch-Reinshagen
authors.forename: James
authors.initials: J
authors.lastname: Donkin
authors.forename: Sophie
authors.initials: S
authors.lastname: Stukas
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chan
authors.forename: Anna
authors.initials: A
authors.lastname: Wilkinson
authors.forename: Jianjia
authors.initials: J
authors.lastname: Fan
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Haydn
authors.initials: H
authors.lastname: Pritchard
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry; D004952:Esters / Q000737:chemistry*; D006801:Humans; D008055:Lipids / Q000134:cerebrospinal fluid / Q000737:chemistry; D008074:Lipoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D017077:Culture Media, Conditioned; D004952:Esters; D008055:Lipids; D008074:Lipoproteins; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase