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Differential effects of 24(S)‐hydroxycholesterol in astrocytes and on the expression of apolipoprotein E and apolipoprotein E‐mediated cholesterol efflux.
Author(s) -
Mulder Monique,
Abildayeva Karlygash,
Jansen Paula,
Ramaekers Frans,
De Vente Jan,
Groen Albert K,
Kuipers Folkert
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a92-c
Subject(s) - liver x receptor , apolipoprotein e , abcg1 , efflux , cholesterol , abca1 , apolipoprotein b , chemistry , endocrinology , biology , microbiology and biotechnology , medicine , transporter , biochemistry , transcription factor , nuclear receptor , gene , disease
Both apolipoprotein E (apoE) and the brain‐specific metabolite of cholesterol 24(S)‐hydroxycholesterol (24(S)‐OH‐chol) are involved in the pathogenesis of Alzheimer’s disease. We show for the first time that the natural Liver‐X‐Receptor (LXR) activator 24(S)‐hydroxycholesterol profoundly regulates apoE expression in astrocytoma but not in neuroblastoma cells. Since the synthetic activator of the LXR, GW683965A (GW) showed a similar effect on apoE expression, both GW and 24(S)‐OH‐chol may act via the same LXR signalling pathway. The proposed mechanism is further substantiated by the observation that the basal LXRa and b expression levels were 10‐20‐fold higher in astrocytoma cells. The apoE‐mediated cholesterol efflux from astrocytoma but not neuroblastoma cells was sstrongly induced by both 24(S)‐OH‐chol and GW. Concommitantly, 24(S)‐OH‐chol and upregulated the expression of ABCG1 in astrocytes suggesting this transporter is involved in cholesterol efflux. Interestingly, only 24(S)‐OH‐chol induced ABCG4 expression in neuronal cells, in which this transporter is already abundantly expressed, but had the opposite effect in astrocytoma cells. Since both compounds induce cholesterol efflux from astrocytes while GW upregulates and 24(S)‐OH‐chol down regulates the expression of HMGCoAR, LDLR and SREBP2 suggests cholesterol efflux and synthesis are independent processes. This strongly suggest that 24(S)‐OH‐chol induces apoE‐mediated cholesterol efflux in astrocytes via an LXR‐controlled pathway.