LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins

Veronica Hirsch-Reinshagen, James Donkin, Sophie Stukas, Jennifer Chan, Anna Wilkinson, Jianjia Fan, John S Parks, Jan Albert Kuivenhoven, Dieter Lütjohann, Haydn Pritchard, Cheryl L Wellington

Research output: Contribution to journalArticleAcademicpeer-review

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)885-93
Number of pages9
JournalJournal of Lipid Research
Volume50
Issue number5
DOIs
Publication statusPublished - May-2009
Externally publishedYes

Keywords

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Animals
  • Apolipoproteins E
  • Astrocytes
  • Cells, Cultured
  • Cholesterol
  • Culture Media, Conditioned
  • Esters
  • Humans
  • Lipids
  • Lipoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons
  • Phosphatidylcholine-Sterol O-Acyltransferase

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