. The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of beta-amyloid precursor protein. J Lipid Res. 2007 May;48(5):1022-34. PubMed.

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  1. Cheryl Wellington and colleagues report that ABCG1 modulates the subcellular distribution and proteolytic processing of β amyloid precursor protein and that ABCG1 mRNA levels are twofold more abundant in Down syndrome brain compared to age- and sex-matched normal controls. The question is raised as to whether ABCG1 may affect the enzymatic activity of the secretases. I wonder whether Kobayashi et al (1) may have helped to answer this with their study finding that ABCG1 is also involved in the efflux of sphingomyelin.

    Studies find that sphingomyelin in rHDL significantly increased efflux only with oleic or linoleic acid-containing rHDLs, compared with efflux without SM (2), while cells cultured with 0.4 mM oleic acid (OA), with 0.1 mM linoleic acid, or with a triglyceride emulsion expressed increased PS1 and Aβ. The increased γ-secretase activity was due the slowing down of presenilin degradation, not to increased PS1 mRNA levels (3). It would seem that by enhancing sphingomyelin efflux, ABCG1 may increase γ-secretase activity.

    The gene for lanosterol synthase is on chromosome 21. Partial inhibition of this enzyme, which resulted in increased 24(S),25-epoxycholesterol, increased ABCA1, ABCG1, and ApoE mRNA abundance and consequently increased cholesterol efflux to apolipoprotein A1 (4). Are the levels 24(S),25-epoxycholesterol increased in DS and AD?

    ABCG1 overexpression in DS would seem to have many implications. It would also seem to explain the lack of atherosclerosis in this population as well as the increased tendency to obesity (5,6).

    References:

    . Efflux of sphingomyelin, cholesterol, and phosphatidylcholine by ABCG1. J Lipid Res. 2006 Aug;47(8):1791-802. PubMed.

    . Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins. Metabolism. 2007 Feb;56(2):251-9. PubMed.

    . Fatty acids increase presenilin-1 levels and [gamma]-secretase activity in PSwt-1 cells. J Lipid Res. 2004 Dec;45(12):2368-76. PubMed.

    . Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in macrophages through increased endogenous synthesis of 24(S),25-epoxycholesterol. J Biol Chem. 2007 Feb 23;282(8):5207-16. Epub 2006 Dec 23 PubMed.

    . Total body ABCG1 expression protects against early atherosclerotic lesion development in mice. Arterioscler Thromb Vasc Biol. 2007 Mar;27(3):594-9. PubMed.

    . Ablation of the cholesterol transporter adenosine triphosphate-binding cassette transporter G1 reduces adipose cell size and protects against diet-induced obesity. Endocrinology. 2007 Apr;148(4):1561-73. Epub 2006 Dec 28 PubMed.