is important, however, to determine whether ABC1 is regulated entirely at the mRNA level or whether its activity might also be regulated by posttranslational modifications, or allosterically, through interaction with specific lipids within the membrane. Implications for plasma lipid metabolismThe discovery of ABC1 has substantial implications for plasma lipoprotein metabolism. ABC1 seems to play an obligatory step in HDL metabolism, transforming lipid-poor apo-AI particles into nascent HDL particles that can interact with the apo-B-containing lipoproteins (for example, low-density lipoproteins) and function in other metabolic processes (panel a of figure). Whether the 'activation' of lipid-poor apo-AI particles involves a direct interaction between ABC1 and apo-AI is unknown and requires investigation. In the absence of ABC1 (panel b of figure), lipid-poor apo-AI particles do not acquire cellular lipids and are therefore cleared rapidly from the plasma 5 . Because the lipid-poor apo-AI particles are not transformed into nascent HDL particles, HDL metabolism never gets off the starting block, and its metabolism is effectively dissociated from that of the apo-B-containing lipoproteins. The low LDL cholesterol levels in the plasma of people with Tangier disease and the triglyceride enrichment of 'Tangier' LDL are almost certainly consequences of this dissociation.Other inherited metabolic defects, such as the loss of ability to generate apo-Bcontaining lipoproteins 14−16 , or loss of ability to transfer polar lipids from very low-density lipoprotein to HDL (ref. 17), seriously perturb HDL metabolism. But respectable levels of HDL (20−50% of normal) still exist in those conditions. That this is not the case in Tangier disease indicates that cell-derived lipids are essential for the production of metabolically competent HDL. Why free cholesterol and phospholipids from the apo-B-containing lipoproteins are apparently incapable of substituting for cellular lipids is perplexing and requires additional investigation.Heterozygotes for ABC1 deficiency have half-normal levels of HDL cholesterol. This was suggested earlier by investigations of the families of people with Tangier disease 5 . In addition, the current study by Michael Hayden and colleagues 2 demonstrates that familial hypoalphalipoproteinaemia (characterized by low HDL cholesterol levels but no overt cholesterol ester accumulation in tissues) can be caused by heterozygous mutation of ABC1.It will be interesting to determine whether subtle polymorphisms in ABC1 contribute to the 10−20% reduction in HDL levels that are so commonly observed in people with atherosclerotic coronary heart disease. In addition, it will be of interest to determine whether ABC1 overexpression in transgenic animals increases HDL cholesterol levels and reduces the accumulation of cholesterol ester-rich macrophages in atherosclerotic plaques. Such a phenotype would obviously make upregulation of ABC1 an attractive goal for the pharmaceutical industrybut predicting the consequences of ABC1 ...
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