Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8.
Mice lacking Niemann-Pick C1-Like 1 (NPC1L1) (NPC1L1(-/-)mice) exhibit a defect in intestinal absorption of cholesterol and phytosterols. However, wild-type (WT) mice do not efficiently absorb and accumulate phytosterols either. Cell-based studies show that NPC1L1 is a much weaker transporter for phytosterols than cholesterol. In this study, we examined the role of NPC1L1 in phytosterol and cholesterol trafficking in mice lacking ATP-binding cassette (ABC) transporters G5 and G8 (G5/G8(-/-) mice). G5/G8(-/-) mice develop sitosterolemia, a genetic disorder characterized by the accumulation of phytosterols in blood and tissues. We found that mice lacking ABCG5/G8 and NPC1L1 [triple knockout (TKO) mice] did not accumulate phytosterols in plasma and the liver. TKO mice, like G5/G8(-/-) mice, still had a defect in hepatobiliary cholesterol secretion, which was consistent with TKO versus NPC1L1(-/-) mice exhibiting a 52% reduction in fecal cholesterol excretion. Because fractional cholesterol absorption was reduced similarly in NPC1L1(-/-) and TKO mice, by subtracting fecal cholesterol excretion in TKO mice from NPC1L1(-/-) mice, we estimated that a 25g NPC1L1(-/-) mouse may secrete about 4 mumol of cholesterol daily via the G5/G8 pathway. In conclusion, NPC1L1 is essential for phytosterols to enter the body in mice.
Tang
Weiqing
W
The 5th Clinical Hospital (Beijing Hospital), Peking University, and Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, Ministry of Health, Beijing, China.
Ma
Yinyan
Y
Jia
Lin
L
Ioannou
Yiannis A
YA
Davies
Joanna P
JP
Yu
Liqing
L
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010840:Phytosterols / Q000097:blood / Q000378:metabolism; D012855:Sitosterols / Q000097:blood* / Q000378:metabolism
C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D010840:Phytosterols; D012855:Sitosterols; D002784:Cholesterol