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 approximately 40% and approximately 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.


CONCLUSIONS
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.
Wang
Helen H
HH
Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard Digestive Diseases Center, Boston, MA, USA.
Patel
Shailendra B
SB
Carey
Martin C
MC
Wang
David Q-H
DQ
D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001646:Bile / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology; D005769:Gastrointestinal Motility / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008074:Lipoproteins / Q000172:deficiency*; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008196:Lymph / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D013261:Sterols / Q000378:metabolism*
C462601:ABCG8 protein, mouse; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D008074:Lipoproteins; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013261:Sterols