Abstract
Mammalian cells have developed various responses to minimize accumulation of unesterified cholesterol, as the latter can result in cell toxicity and death [reviewed in this edition by Björkhem (Björkhem, I. 2009. Are side-chain oxidized oxysterols regulators also in vivo? J. Lipid Res. In press)]. These responses include esterification to sequester excess sterol in intracellular lipid droplets, repression of both cholesterol synthesis and LDL receptor expression (thus reducing endocytosis of LDL), and induction of a panoply of genes that promote sterol efflux and affect lipid metabolism. The nuclear receptor liver-X-receptor (LXR) functions as a cellular "sterol sensor" and plays a critical role in these latter transcriptional changes [reviewed in this edition by Glass (Shibata, N., and Glass C, K. 2009. Regulation of macrophage function in inflammation and atherosclerosis. J. Lipid Res. In press)]. Activation of LXR by either endogenous oxysterols or synthetic agonists induces the expression of many genes, including those encoding ATP-binding cassette (ABC) transporters ABCA1, ABCG1, ABCG5, and ABCG8. As discussed below, these four proteins function to promote sterol efflux from cells.
Highlights
Mammalian cells have developed various responses to minimize accumulation of unesterified cholesterol, as the latter can result in cell toxicity and death [reviewed in this edition by Björkhem
In agreement with this proposal, deposition of brain amyloid protein in amyloid precursor protein transgenic mice was increased or decreased following either deletion or overexpression of ABCA1, respectively [15]. These results suggest that ABCA1 plays a critical role in amyloidogenesis, and, it has been proposed that pharmacological intervention in the ABCA1/apoE/amyloid protein axis might prove useful in the control of Alzheimers disease (AD) [15]
A two-step process has been proposed in which ABCA1 initially promotes lipidation of lipid-poor apo-proteins, and ABCG1 subsequently facilitates a further enrichment with cholesterol
Summary
Mammalian cells have developed various responses to minimize accumulation of unesterified cholesterol, as the latter can result in cell toxicity and death [reviewed in this edition by Björkhem It is well accepted that: i) ABCA1 is expressed in multiple cells and tissues (Fig. 1); ii) the gene is highly induced following activation of LXR; iii) ABCA1 protein localizes to both the plasma membrane and intracellular vesicles; and iv) ABCA1 promotes the efflux of phospholipids and cholesterol to lipid-poor apoproteins, such as apoA1, so as to generate preb HDL [2].
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