Familial HDLdeficiency and ABCA1

The major clue that ABCA1 is involved in cellular cholesterol removal and lipid efflux was the identification of mutations in the human gene as the defect in familial HDL-deficiency syndromes such as classical Tangier disease (Tab. 3.2) [6-8]. The most striking feature of these patients is the almost complete absence of plasma HDL, low serum cholesterol levels, and a markedly reduced efflux of both cholesterol and phospholipids from cells, strongly supporting the idea that both lipids are co-transported [128, 129]. The lack of ABCA1 function in these patients has a major impact on plasma HDL levels and composition. Thus plasma HDL from TD patients is composed of small pre-/5rmigrating HDL particles containing solely apoAI and phospholipids but lacking free cholesterol and apoAII [130, 131]. The low HDL levels seen in Tangier disease (TD) are mainly due to an enhanced catabolism of these HDL precursors [131-134]. In addition, the size of the HDL

particle strongly correlates with the amount of cholesterol efflux and plasma HDL concentrations [135, 136]. In TD patients, neither cholesterol absorption nor metabolism is significantly affected, however, the concentration of LDL-cholesterol is only 40% of healthy controls and the particles are often enriched in triglycerides. The reduction in LDL levels is mainly caused by disturbance of the cholesterol ester transfer pathway resulting in changes of LDL composition and size [137].

Interestingly, obligate heterozygotes for TD mutations have approximately 50% of plasma HDL, but normal LDL levels [138]. Studying 13 different mutations in 77 heterozygous individuals, Clee et al. described a more than 3-fold risk of developing coronary artery disease in affected family members and earlier onset compared with unaffected members [139, 140]. However, these results seem to be biased towards the atherosclerotic phenotype, since the prevalence of splenomegaly is much higher in the European group of ABCA1 deficiency patients [46]. These authors also reported an age-dependent modification of the ABCA1 heterozygous phenotype [140].

In addition to the absence of plasma HDL, patients with genetic HDL-deficien-cy syndromes display accumulation of cholesteryl esters either in the cells of the reticulo-endothelial system (RES), leading to splenomegaly and enlargement of tonsils or lymph nodes, or in the vascular wall, leading to premature atherosclerosis [46]. This indicates differences in macrophage trafficking into tissues in the absence of ABCA1 which may be a reflection of the specific localization of mutations within the ABCA1 gene. In this context, it is of note that the pool size of CD14dimCD16+ monocytes is inversely correlated with plasma HDL-cholesterol levels [141] and the expression of ABCA1 is high in phagocytes [40] but low in antigen-presenting dendritic precursor cells (unpublished observation). These observations may provide clues for a potential interlink between ABCA1 function and the control of monocyte differentiation and phagocyte/dendritic cell lineage commitment. Accordingly, we have previously hypothesized that ABCA1 function regulates the differentiation, lineage commitment (phagocytic versus dendritic cells), and targeting of monocytes into the vascular wall of the RES [142]. This concept has been substantiated by recent work from our laboratory demonstrating accumulation of macrophages in liver and spleen in LDL receptor-deficient mouse chimeras that selectively lack ABCA1 in their blood cells [143]. The fact that the absence of ABCA1from leukocytes is sufficient to induce aberrant monocyte recruitment into specific tissues identifies ABCA1 as a critical leukocyte factor in the control of monocyte targeting.

In addition to phagocytes, dendritic cells have been shown to be increased in atherosclerotic lesions and have been implicated in T cell activation in atherogen-esis [144]. Expression of ABCA1 appears to inhibit monocyte differentiation into macrophages and may thus shift the balance between phagocytic differentiation and dendritic cell differentiation towards the latter [145]. Taking into account that dendritic cells are capable of inducing primary immune responses, ABCA1 may function, through this mechanism, as a modulator of innate immunity in athero-genesis. An interesting clue as to how ABCA1 may be implicated in the control of monocyte/macrophage trafficking at the cellular level comes from the observation that apoAI-mediated lipid efflux in ABCAl-deficient cells is paralleled by the downregulation of the protein Cdc42 and filopodia formation [146]. Cdc42, like rho and rac, is a member of the family of small GTP binding proteins which are sequentially activated by extracellular stimuli in mammalian cells [147]. Cdc42 controls a wide range of cellular functions including cytoskeletal modulation, formation of filopodia and vesicular processing. Rho proteins are known to induce the formation of stress fibers and focal adhesions; rac proteins regulate formation of lamellipodia and membrane ruffles. It is thus tempting to speculate that ABCA1 modulates cellular mobility of monocytes/macrophages through this mechanism and thus may affect recruitment of monocytes into the vessel wall. This regulator function for filopodia formation and cytoskeletal reorganization may even extend to platelet aggregation, vascular smooth muscle cell migration, and endothelial cell integrity, since these cells have been shown to express ABCA1 [148].

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