Accumulation of Dietary Cholesterol in Sitosterolemia Caused by Mutations in Adjacent ABC Transporters

TLDR

Sitosterolemia is an autosomal recessive disorder that, unlike normal individuals, shows markedly increased intestinal absorption and decreased biliary excretion of dietary sterols, leading to hypercholesterolemia and early coronary atherosclerosis. The study identified seven pathogenic mutations in the adjacent ABC transporter genes ABCG8 (six) and ABCG5 (one) in nine sitosterolemia patients. ABCG5 and ABCG8 are highly expressed in liver and intestine, are up‑regulated by dietary cholesterol, and normally cooperate to restrict intestinal absorption and promote biliary excretion; loss‑of‑function mutations in these transporters cause sterol accumulation and atherosclerosis.

Abstract

In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, 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) transporter family (six mutations in ABCG8 and one in ABCG5 ) in nine patients with 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, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.