"Tangier disease is an inherited disorder that results in a deficiency in circulating levels of HDL. Although the disease is known to be caused by mutations in the ABCA1 gene, the mechanism by which lesions in the ABCA1 ATPase effect this outcome is not known. The inability of ABCA1 knockout mice (ABCA1−/−) to load cholesterol and phospholipids onto apoA1 led to a proposal that ABCA1 mediates the transbilayer externalization of phospholipids, an activity integral not only to the formation of HDL particles but also to another, distinct process: the recognition and clearance of apoptotic cells by macrophages. Expression of phosphatidylserine (PS) on the surface of both macrophages and their apoptotic targets is required for efficient engulfment of the apoptotic cells, and it has been proposed that ABCA1 is required for transbilayer externalization of PS to the surface of both cell types. To determine whether ABCA1 is responsible for any of the catalytic activities known to control transbilayer phospholipid movements, these activities were measured in cells from ABCA1−/− mice and from Tangier individuals as well as ABCA1-expressing HeLa cells. Phospholipid movements in either normal or apoptotic lymphocytes or in macrophages were not inhibited when cells from knockout and wildtype mice or immortalized cells from Tangier individuals vs normal individuals were compared. Exposure of PS on the surface of normal thymocytes, apoptotic thymocytes and elicited peritoneal macrophages from wildtype and knockout mice or B lymphocytes from normal and Tangier individuals, as measured by annexin V binding, was also unchanged. No evidence was found of ABCA1-stimulated active PS export, and spontaneous PS movement to the outer leaflet in the presence or absence of apoA1 was unaffected by the presence or absence of ABCA1. Normal or Tangier B lymphocytes and macrophages were also identical in their ability to serve as targets or phagocytes, respectively, in apoptotic cell clearance assays. No evidence was found to support the suggestion that ABCA1 is involved in transport to the macrophage cell surface of annexins I and II, known to enhance phagocytosis of apoptotic cells. These results show that mutations in ABCA1 do not measurably reduce the rate of transbilayer movements of phospholipids in either the engulfing macrophage or the apoptotic target, thus discounting catalysis of transbilayer movements of phospholipids as the mechanism by which ABCA1 facilitates loading of phospholipids and cholesterol onto apoA1."This article is heavy on the biochemical pathways of the ABCA1 gene, which is thought to have an important role in the formation of "good cholesterol" or High Density Lipoprotein (HDL). One mutation in this region leads to the autosomal genetic disorder called Tangier Disease and another mutation leads to Familial Hypoalphalipoproteinemia and both reduce levels of HDL produced in the body. This often leads to premature cardiovascular disease and is considered that mutations in this gene are the leading cause of early Atherosclerosis. The gene is highly conserved between species (Singaraja et al. 2003). However, in humans the ABCA1 genes is thought to have undergone intense positive selection and is thought to be comparable to the FOXP2 language acquisition gene (Brunham et al. 2006). This latter fact has always intrigued me as to why this intense selection on a gene involved in lipid metabolism and is it associated with diet. Anyway back to the matter of hand. The prevailing theory of ABCA1 metabolism is that involves the transfer of a particular phospholipid (phosphatidylserine) across cell membranes. The Williamson et al. (2007) article refutes that hypothesis and instead suggests that ABCA1 is involved in placing the phospolipid on to the APOa molecule.
The second Science Daily news story is a little less esoteric and investigates Waist-to-hip Ratio May Better Predict Cardiovascular Risk Than Body Mass Index about a study that investigates the efficacy of BMI vs girth basically. BMI is easy to measure but as a predictor of function in CVDs it is pretty much worthless.
References
| Brunham LR, Singaraja RR, Hayden MR (2006) Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis. Annu Rev Nutr. ;26:105-29. Review. |
Singaraja RR, LR Brunham, H Visscher, JJP (2003) "Efflux and Atherosclerosis The Clinical and Biochemical Impact of Variations in the ABCA1 Gene- Arteriosclerosis, Thrombosis, and Vascular Biology, - Am Heart Assoc
