Quantifying anomalous intestinal sterol uptake, lymphatic transport, and biliary secretion in Abcg8 −/− mice

Sitosterolemia is caused by mutations in either ABCG5 or ABCG8 , but simultaneous mutations of these genes have never been observed. To explore whether ABCG8, the sterol efflux (hemi‐)transporter, plays a major role in determining intestinal absorption efficiency and hepatic secretion rates of cholesterol and sitostanol, we performed direct measurements of the absorption and lymphatic transport of these sterols in mice with chronic biliary and lymphatic fistulae, as well as the transport rates of radiolabeled cholesterol and sitostanol from plasma high‐density lipoprotein (HDL) into bile in male Abcg8 −/− and wild‐type mice. We observed that the absorption and lymphatic transport rates of radiolabeled cholesterol and sitostanol were increased by ≈40% and ≈500%, respectively, in Abcg8 −/− mice in the setting of constant intraduodenal infusion of micellar taurocholate and lecithin. Both strains displayed identical intestinal Npc1l1 expression levels and small intestinal transit rates. After 45 minutes of intraduodenal infusion, acute intestinal uptake rates of trace [ 14 C]cholesterol and [ 3 H]sitostanol were essentially similar in both groups of mice with intact biliary secretion. Furthermore, in wild‐type mice, mass transport rate of [ 3 H]sitostanol from plasma HDL into bile was significantly faster than that of [ 14 C]cholesterol; however, no [ 3 H]sitostanol and only traces of [ 14 C]cholesterol were detected in bile of Abcg8 −/− mice. Conclusion: Deletion of the Abcg8 gene alone significantly increases the mass of intestinal cholesterol and sitostanol absorption and reduces but does not eliminate hepatic secretion of cholesterol. Moreover, the mutation has no influence on acute uptake of cholesterol and sitostanol by the enterocyte nor small intestinal transit time. (H EPATOLOGY 2007;45:998–1006.)