*3.1. Role of ABCA7 in Lipid Release and Trafficking*

As indicated above, ABCA7 shares high amino sequence homology with other ABC transporters mediating lipid release from cell membranes, and in particular with ABCA1. This latter is the most studied ABC transporter in this cellular process and its role in cholesterol efflux to high-density lipoproteins (HDL) is very well characterized [29–31]. Mutations in the *ABCA1* gene cause an inherited disease named Tangier disease in which the cholesterol transfer from cells to HDL is decreased, leading to lower ApoA-I synthesis as well as low levels of plasmatic HDL [32]. Consequently, this lipid homeostasis imbalance promotes lipid accumulation inside vascular cells and macrophages, thus provoking coronary artery disease and atherosclerosis in patients [27,33,34].

On this basis, *Abca7*−/<sup>−</sup> mice were generated to further characterize the role of this ABC transporter in cholesterol metabolism. Interestingly, only transgenic female mice showed slight abnormalities in their cholesterol metabolism when compared with the wildtype littermates [16]. Indeed, female *Abca7*−/<sup>−</sup> mice showed weight gain identical to female controls but less white adipose tissue, plasmatic HDL and cholesterol [16]. No significant differences have been measured in males. In the same study, no alteration of the cholesterol or phospholipid efflux was measured in macrophages purified from the *Abca7*−/<sup>−</sup> mice. However, further in vitro studies using different transfected cell types reported that ABCA1, ABCA7 binds ApoA-I, and ApoE, to transfer cholesterol and to generate HDL [18–20]. Of note, this efflux is marginal when compared with cholesterol efflux mediated by ABCA1. On the contrary, ABCA7 is more prone to transfer phospholipids to HDL, in particular sphingomyelin, and (lyso)phosphatidylcholine [18,19,35]. Importantly, almost all of these studies were done by artificially upregulating or downregulating *Abca7* expression that, in turn, provokes a modification of ABCA1 expression, probably by a compensatory mechanism [20,36]. This effect is also reciprocal because the decrease of *Abca1* expression increases *Abca7* level [37]. Abe-Dohmae et al. demonstrated that this compensatory mechanism allows the transfer of cholesterol to lipoproteins when the *Abca1* gene is deficient or absent [35]. However, it remains still unknown why ABCA7 cannot compensate this deficiency in a Tangier disease patient. In light of all these data, it is now widely accepted that ABCA7 is specialized in phospholipid transfer to HDL whereas ABCA1 releases cholesterol.

It is also clear that *Abca7* transcriptional expression is closely regulated by cholesterol metabolism. BALB/3T3 cells loaded with cholesterol showed a significant downregulation of *Abca7* whereas an upregulation of *Abca1* was observed [37]. On the contrary, cholesteroldepleted cells displayed increased *Abca7* expression. In fact, ABCA7 expression is regulated by the sterol-responsive/regulatory element binding protein (SREBP), able to bind specific sterol regulatory element DNA sequences when mammalian cells lack cholesterol, thus triggering the expression of the mRNA of genes involved in cholesterol synthesis or lipoprotein uptake such as HMG-CoA reductase or LDLR, respectively [37]. Blocking HMG-CoA reductase activity with statins, thus blocking cholesterol synthesis, activates SREBP nucleus translocation and increases ABCA7 expression in murine macrophages [38]. Interestingly, *ABCA1* expression is controlled by the Liver X receptor (LXR) nuclear receptors [39], also acting as cholesterol sensors in mammalian cells, thus probably explaining why ABCA1 and ABCA7 expressions are regulated differently to modulate the intracellular pool of cholesterol.

ABCA7 is also implicated in lipid trafficking during keratinocyte differentiation and is reported as a ceramide homeostasis regulator. ABCA7 upregulation was detected in normal human epidermal keratinocytes and HaCaT cells undergoing in vitro differentiation in parallel with an increase in intracellular ceramide levels. In accordance with these results, ABCA7 overexpression in Hela cells showed a ceramide de novo synthesis activation with an increase in intracellular and cell surface ceramide expression [40].

Altogether, these data reinforced the hypothesis that ABCA1 and ABCA7 are closely linked to regulate the cellular lipid metabolism but the role of ABCA7 seems to be rather indirect or negligible when directly compared to ABCA1.
