The ABCs of cholesterol efflux

• Published in: Nature genetics Vol. 22; no. 4; pp. 316 - 318
• Main Authors: Young, Stephen G, Fielding, Christopher J
• Format: Journal Article
• Language: English
• Published: United States 01.08.1999
• Subjects: ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - metabolism; Child, Preschool; Cholesterol - blood; Cholesterol - physiology; Glycoproteins - metabolism; Humans; Lipoproteins, HDL - blood; Male; Membrane Glycoproteins - metabolism; Membrane Lipids - metabolism; Models, Biological; Tangier Disease - metabolism
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/11878

Orange tonsils, peripheral neuropathy and a virtual absence of high-density lipoprotein (HDL) cholesterol are the key findings of Tangier disease. Since the early 1960s, when this disease (which is recessive) was first described, medical students have memorized this constellation of findings for their exams. Concurrently, investigators have sought to determine its cause, convinced that their efforts would yield a treasure trove for the lipid- and lipoprotein-metabolism field. Deciphering the disease was clearly important, as low levels of HDL are linked to the development of coronary heart disease. Now, groups led by Michael Hayden, Gerd Schmitz and Gerd Assmann (see pages 336, 347 and 352) have unearthed riches in the form of mutations in the ATP-binding-cassette transporter 1 gene (ABC1) in people with Tangier disease. Tangier disease was identified in a five-year-old boy born and raised on Tangier Island, Virginia--basically, a large sand bar in the middle of Chesapeake Bay. Settled by a few English watermen in the 1680s, the island has remained a secluded enclave for centuries. It was occasionally the haunt of pirates, and its population was sporadically decimated by pestilence. More than three centuries after the arrival of the initial settlers, its inhabitants still speak a unique Elizabethan dialect, and three-quarters of them bear one of four surnames from the original group of founders. It is not particularly surprising, therefore, that a recessive disease would eventually occur in this locale. The first people with Tangier disease made their way from Chesapeake Bay to the National Institutes of Health (NIH), where the orange colour of their tonsils was shown to be caused by an accumulation of cholesterol esters (and associated carotenoids) in macrophages. Their plasma concentrations of apolipoprotein (apo-) AI, the principal constituent protein of HDL, were very low, and HDL cholesterol was virtually absent from the plasma. The combination of low plasma HDL cholesterol levels and cellular cholesterol ester accumulation was intriguing in light of the proposed role of HDL in unloading cholesterol from cells and transporting it back to the liver (reverse cholesterol transport).