Disruption of <i>Abcg5</i> and <i>Abcg8</i> in mice reveals their crucial role in biliary cholesterol secretion

TLDR

Cholesterol and other sterols are primarily eliminated by bile secretion, and mutations in ABCG5 or ABCG8 that reduce sterol excretion in sitosterolemia implicate these transporters in the process. The study aimed to determine the roles of ABCG5 and ABCG8 in sterol trafficking. The authors disrupted Abcg5 and Abcg8 in mice to generate G5G8−/− animals. G5G8−/− mice exhibited markedly increased plant sterol absorption and plasma sitosterol, severely reduced biliary cholesterol, and a 50 % drop in plasma and liver cholesterol on chow that rose sharply with dietary cholesterol, demonstrating that ABCG5/8 are essential for bile cholesterol secretion and that their loss heightens cholesterol responsiveness to diet.

Abstract

Cholesterol and other sterols exit the body primarily by secretion into bile. In patients with sitosterolemia, mutations in either of two ATP-binding cassette (ABC) half-transporters, ABCG5 or ABCG8, lead to reduced secretion of sterols into bile, implicating these transporters in this process. To elucidate the roles of ABCG5 and ABCG8 in the trafficking of sterols, we disrupted Abcg5 and Abcg8 in mice ( G5G8 −/− ). The G5G8 −/− mice had a 2- to 3-fold increase in the fractional absorption of dietary plant sterols, which was associated with an ≈30-fold increase in plasma sitosterol. Biliary cholesterol concentrations were extremely low in the G5G8 −/− mice when compared with wild-type animals (mean = 0.4 vs. 5.5 μmol/ml) and increased only modestly with cholesterol feeding. Plasma and liver cholesterol levels were reduced by 50% in the chow-fed G5G8 −/− mice and increased 2.4- and 18-fold, respectively, after cholesterol feeding. These data indicate that ABCG5 and ABCG8 are required for efficient secretion of cholesterol into bile and that disruption of these genes increases dramatically the responsiveness of plasma and hepatic cholesterol levels to changes in dietary cholesterol content.