TY - JOUR
T1 - Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8
AU - Tang, Weiqing
AU - Ma, Yinyan
AU - Jia, Lin
AU - Ioannou, Yiannis A.
AU - Davies, Joanna P.
AU - Yu, Liqing
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009
Y1 - 2009
N2 - 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 μmol of cholesterol daily via the G5/G8 pathway. In conclusion, NPC1L1 is essential for phytosterols to enter the body in mice.
AB - 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 μmol of cholesterol daily via the G5/G8 pathway. In conclusion, NPC1L1 is essential for phytosterols to enter the body in mice.
KW - ATP-binding cassette
KW - Niemann-Pick C1-Like 1
KW - Phytosterols
KW - Sterol absorption
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U2 - 10.1194/jlr.M800439-JLR200
DO - 10.1194/jlr.M800439-JLR200
M3 - Article
C2 - 18796403
AN - SCOPUS:64749088618
SN - 0022-2275
VL - 50
SP - 293
EP - 300
JO - Journal of lipid research
JF - Journal of lipid research
IS - 2
ER -