Molecular defects in the ABCA1 pathway affect platelet function

Platelet function is sensitive to alterations in cholesterol metabolism, and hypercholesterolemia is associated with enhanced platelet reagibility. Atherogenic low-density lipoproteins (LDL), in particular oxidized LDL, activate src-kinase-family-dependent signalling. In contrast, antiatherogenic high-density lipoproteins (HDL) inhibit platelet aggregation and target the phosphatidylinositol phospholipase C (PI-PLC) pathway. Sphingosine 1-phosphate is a major HDL-component and may be crucial for downstream reactions of collagen-induced glycoprotein VI signalling and phosphoinositide 3-kinase. The ATP-binding cassette transporter A1 (ABCA1) regulates cell membrane phospholipid and cholesterol homeostasis and their release to lipid-poor apolipoprotein A1 to generate prep-HDL precursor particles. ABCA1 also interacts with modulators of vesicular trafficking and ABCA1 deficiency is associated with a reduced number and impaired release of dense bodies from platelets. The ABCA1-NH2-terminus-associated Syntaxin 13, a SNARE complex protein, interacts with syntaxin 13-interacting protein (pallidin) whose deficiency leads to impaired platelet granule release from the dense granule Adapter Protein-3 (AP-3)-related pathway. Interestingly, the cholesterol transporter ABCG1 in addition to ABCA1 is another constituent of the AP-3 pathway, and disorders of lysosome-related organelles such as the Hermansky-Pudlack-syndrome complex, Chediak-Higashi syndrome and the ceroid lipofuscinoses provide new opportunities to understand AP-3 pathway-related disorders and their relation to membrane phospholipid processing. ABCA1 mutations are involved in dysregulated vesicular trafficking from the transgolgi compartment to the plasma membrane, and ABCA1 R1925Q was shown to contribute to Scott syndrome, a phospholipid-processing disorder of missing surface exposure of phosphatidlyserine. The P2Y12 receptor triggers dense granule secretion by downstream effectors including the G-protein-coupled inward rectifier K+ channel-4 (GIRK-4), and we found the sister gene GIRK-3 associated with the ABCA1 protein in macrophages. It is concluded that the presence of ABCA1 and ABCG1 in the AP-3 pathway will have major impact for membrane phospholipid processing and HDL metabolism and their relation to disorders of lysosome-related organelles. Copyright (c) 2006 S. Karger AG, Basel.