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Cited by 153Cholesterol and Lipid MetabolismDrug Transport and Resistance MechanismsAlzheimer's disease research and treatments

Cholesterol efflux is differentially regulated in neurons and astrocytes: Implications for brain cholesterol homeostasis

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Chen, Jing, Zhang, Xiaolu, Kusumo, Handojo, Costa, Lucio G., Guizzetti, Marina·2013·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
DOI 10.1016/j.bbalip.2012.09.007PMC PMC3534809
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Abstract

Disruption of cholesterol homeostasis in the central nervous system (CNS) has been associated with neurological, neurodegenerative, and neurodevelopmental disorders. The CNS is a closed system with regard to cholesterol homeostasis, as cholesterol-delivering lipoproteins from the periphery cannot pass the blood-brain-barrier and enter the brain. Different cell types in the brain have different functions in the regulation of cholesterol homeostasis, with astrocytes producing and releasing apolipoprotein E and lipoproteins, and neurons metabolizing cholesterol to 24(S)-hydroxycholesterol. We present evidence that astrocytes and neurons adopt different mechanisms also in regulating cholesterol efflux. We found that in astrocytes cholesterol efflux is induced by both lipid-free apolipoproteins and lipoproteins, while cholesterol removal from neurons is triggered only by lipoproteins. The main pathway by which apolipoproteins induce cholesterol efflux is through ABCA1. By upregulating ABCA1 levels and by inhibiting its activity and silencing its expression, we show that ABCA1 is involved in cholesterol efflux from astrocytes but not from neurons. Furthermore, our results suggest that ABCG1 is involved in cholesterol efflux to apolipoproteins and lipoproteins from astrocytes but not from neurons, while ABCG4, whose expression is much higher in neurons than astrocytes, is involved in cholesterol efflux from neurons but not astrocytes. These results indicate that different mechanisms regulate cholesterol efflux from neurons and astrocytes, reflecting the different roles that these cell types play in brain cholesterol homeostasis. These results are important in understanding cellular targets of therapeutic drugs under development for the treatments of conditions associated with altered cholesterol homeostasis in the CNS.

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Authors
Chen, J., Zhang, X., Kusumo, H., Costa, L. G., & Guizzetti, M.
Affiliations
  • University of Washington (US)
  • University of Illinois Chicago (US)
  • University of Parma (IT)
Corresponding author
Guizzetti, Marina
ORCID
Venue
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Publisher
Elsevier BV
Published
2013-02
Volume
1831
Issue
2
Pages
263-275
ISSN
1388-1981 (ISSN-L)
DOI
10.1016/j.bbalip.2012.09.007
PMC
PMC3534809
OpenAlex
W1978679668
Cited by
153
References
3
Citations by year
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FWCI
7.84
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
National Institute of Alcoholism and Alcohol Abuse (AA017180)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
cholesterol efflux, brain cholesterol homeostasis, astrocytes, neurons, ABCA1, ABCG1, ABCG4, apolipoprotein E, lipoproteins, 24S-hydroxycholesterol, blood-brain barrier, neurodegenerative diseases
MeSH terms
ATP Binding Cassette Transporter, Subfamily G, Member 1, Animals, Astrocytes, Biological Transport, Brain, Cells, Cultured, Cholesterol, Homeostasis, Neurons, Blotting, Western, Rats, Sprague-Dawley, ATP-Binding Cassette Transporters, Rats, Real-Time Polymerase Chain Reaction, ATP Binding Cassette Transporter 1

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