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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1423.)
© 2000 American Heart Association, Inc.

Editorials

A, B, C...!

Alan R. Tall; Christian W. Schindler

From the Departments of Medicine (A.R.T., C.W.S.) and Microbiology (C.W.S.), Columbia University, New York.

Correspondence to Alan R. Tall, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032.

Key Words: ABC1 • LXR • HDL • foam cell • atherosclerosis

Tangier disease is a rare recessive genetic disorder, characterized by extremely low HDL levels, accumulation of cholesterol esters in macrophages, and premature coronary heart disease.¹ The observation that fibroblasts from Tangier disease patients have a marked defect in efflux of cholesterol and phospholipids to apoA-I provided a key insight into the underlying defect.² Recently, 3 different groups made the exciting discovery that Tangier disease is caused by mutations in an adenosine triphosphate (ATP) binding cassette transporter, ABC1.^{3 4 5} Thus, it is likely that ABC1 mediates or regulates the efflux of cellular cholesterol and phospholipids to apoA-I. Although ABC1 is widely expressed, the brunt of the defect is seen in macrophages, indicating their absolute dependence on an active cholesterol efflux pathway. The nature of the ABC1 molecule and the consequences of its mutation provide important evidence that reverse cholesterol transport underlies the atheroprotective effect of HDL. Already a multiplicity of ABC1 mutations have been described.^{3 4 5} Importantly, heterozygous mutations can also cause the more common forms of familial hypoalphalipoproteinemia.⁴

The ABC1 molecule contains 2 clusters of 6 transmembrane domains and internal loops with nucleotide binding motifs. Similar ABC transporters have been described to act as phospholipid flippases, ie, they utilize ATP to transfer phospholipids from the inner to the outer leaflet of cellular membranes.⁶ Although ABC1 is expressed in the plasma membrane,⁷ it could also be active at intracellular sites such as the golgi. Based on a detailed electron microscopic analysis of a related ABC transporter, the multidrug resistance P-glycoprotein, it is likely . . . [Full Text of this Article]