LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins.
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.
Hirsch-Reinshagen
Veronica
V
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
Donkin
James
J
Stukas
Sophie
S
Chan
Jennifer
J
Wilkinson
Anna
A
Fan
Jianjia
J
Parks
John S
JS
Kuivenhoven
Jan Albert
JA
Lütjohann
Dieter
D
Pritchard
Haydn
H
Wellington
Cheryl L
CL
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*
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