BBALIP-12-73R1_Submitted to Indigo.pdf (485.57 kB)
0/0

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

Download (485.57 kB)
journal contribution
posted on 03.01.2014 by Jing Chen, Xiaolu Zhang, Handojo Kusumo, Lucio G. Costa, Marina Guizzetti
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.

Funding

This work was supported by grant AA017180 from the National Institute of Alcoholism and Alcohol Abuse.

History

Publisher Statement

NOTICE: This is the author’s version of a work that was accepted for publication in Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids, Vol 1831, Issue 2, 2013 DOI:10.1016/j.bbalip.2012.09.007

Publisher

Elsevier Inc.

Language

en_US

issn

1388-1981

Issue date

01/02/2013

Exports

Categories

Exports