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Papers In Press, published online ahead of print March 8, 2006
Dept. of Molecular Cell Biology, University of Maastricht, Maastricht 6200 MD
Corresponding Author: M.Mulder{at}MOLCELB.unimaas.nl
Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer's disease (AD). It has been hypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-containing high density lipoproteins (HDL) remains to be clarified. We show, for the first time, that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol induces apoE transcription, protein synthesis and secretion in a dose- and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic Liver-X-Receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signalling pathway. A 10- to 20-fold higher basal LXR± and = expression level in astrocytoma compared to neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP-binding cassette transporters ABCA1 and ABCG1, since their expression was also upregulated by both compounds. In contrast, ABCG4 seems not to be involved, as its expression was induced only in neuronal cells. The expression of SREBP-2, LDLR, HMGCoA-Reductase and SREBP-1c was transiently upregulated by GW683965A in astrocytes, but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurological diseases.
J. Biol. Chem, 10.1074/jbc.M601019200
Submitted on February 2, 2006
Accepted on March 8, 2006
24(S)-Hydroxycholesterol participates in a Liver X Receptor-controlled pathway in astrocytes that regulates Apolipoprotein E-mediated cholesterol efflux
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