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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M800584-JLR200 on December 8, 2008

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Journal of Lipid Research, Vol. 50, 885-893, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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{dagger}, Jan Albert Kuivenhoven§, Dieter Lütjohann**, Haydn Pritchard* and Cheryl L. Wellington1,*

* Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
{dagger} Department of Pathology/Section on Lipid Sciences, Wake Forest University Health Sciences, Winston-Salem, NC
§ Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
** Institute of Clinical Chemistry and Pharmacology, University of Bonn, Bonn, Germany

JD is supported by the Arthur and June Willms Postdoctoral fellowship at the University of British Columbia, JP is supported by NIH grants HL54176 and HL49373, JAK is supported by a grant of the European Community (FP6-2005-LIFESCIHEALTH-6; STREP contract number 037631), and CLW is supported by a Canadian Institutes of Health Research New Investigator Award. Operating funding for this work was provided by the Heart and Stroke Foundation of Canada to HP and CLW.

Published, JLR Papers in Press, December 8, 2008.

1 To whom correspondence should be addressed. e-mail: cheryl{at}cmmt.ubc.ca

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 ~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.

Supplementary key words central nervous system • HDL • apoE • apoA-I • ABCA1 • mouse • lipoprotein metabolism

Abbreviations: ACM, astrocyte-conditioned media; apoA-I, apolipoprotein A-I; apoE, apolipoprotein E; BHK, baby hamster kidney cells; CE, cholesterol esters; CNS, central nervous system; CSF, cerebrospinal fluid; EYPC, egg yolk phosphatidylcho1ine; GCM, glia-conditioned media; MER, molar esterification rate of cholesterol; NCM, neuronal conditioned media; qRT-PCR, quantitative RT-PCR; UC, unesterified cholesterol; WT, wild-type


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