24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

Karlygash Abildayeva,Paula J Jansen,Veronica Hirsch-Reinshagen,Vincent W Bloks,Arjen H.F Bakker,Frans C.S Ramaekers,Jan De Vente,Albert K Groen,Cheryl L Wellington,,Folkert Kuipers,Monique Mulder

doi:10.1074/jbc.m601019200

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.

Highlights

Disturbances in brain cholesterol homeostasis are associated with the onset of severe neurological diseases [1] and have recently been suggested to play a key role in the development of Alzheimer disease (AD)4 [2, 3]
We found that 24(S)-hydroxycholesterol, like GW683965A, is able to induce the expression of ATP binding cassette transporters A1 (ABCA1), ABCG1, and apoE in astrocytes and to elevate apoE-mediated cholesterol efflux in astrocytoma but not in neuroblastoma cells
The established liver X receptors (LXR) target gene SREBP-1c was induced by both compounds but displayed a different induction profile compared with apoE (Fig. 2B)

Summary

Introduction

Disturbances in brain cholesterol homeostasis are associated with the onset of severe neurological diseases [1] and have recently been suggested to play a key role in the development of Alzheimer disease (AD)4 [2, 3]. For this purpose the effects of 24(S)-hydroxycholesterol and the synthetic LXR agonist GW683965A on the expression of apoE and additional LXR target genes involved in cholesterol efflux were compared using human neuroblastoma and astrocytoma cell lines as well as primary astrocytes. We found that 24(S)-hydroxycholesterol, like GW683965A, is able to induce the expression of ABCA1, ABCG1, and apoE in astrocytes and to elevate apoE-mediated cholesterol efflux in astrocytoma but not in neuroblastoma cells.

Results

Conclusion