title: 24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux.
abstract: Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer 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 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 signaling pathway. A 10-20-fold higher basal LXRalpha and -beta expression level in astrocytoma compared with 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 up-regulated by both compounds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated 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.
authors.affiliation: Department of Molecular Cell Biology, Institute of Brain and Behavior (European Graduate School of Neuroscience, EURON), University of Maastricht, 6200 MD Maastricht, The Netherlands.
authors.forename: Karlygash
authors.initials: K
authors.lastname: Abildayeva
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Jansen
authors.forename: Veronica
authors.initials: V
authors.lastname: Hirsch-Reinshagen
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.forename: Arjen H F
authors.initials: AH
authors.lastname: Bakker
authors.forename: Frans C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Jan
authors.initials: J
authors.lastname: de Vente
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Monique
authors.initials: M
authors.lastname: Mulder
mesh_terms: D000070996:ATP Binding Cassette Transporter, Subfamily G; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry* / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
chemical_list: C439766:ABCG4 protein, human; D000070996:ATP Binding Cassette Transporter, Subfamily G; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; C044563:24-hydroxycholesterol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases