Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters

In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitost erolemia, an autosomal recessive disorder characterized by increased intest inal absorption and decreased biliary excretion of dietary sterols, hyperch olesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) tran sporter family (six mutations in ABCG8 and one in ABCG5) in nine patients w ith sitosterolemia. The two genes are expressed at highest levels in Liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to Limit intestinal absorption and to promote biliary excretion of sterols, an d that mutated forms of these transporters predispose to sterol accumulatio n and atherosclerosis.