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Journal of Lipid Research, Vol. 50, 293-300, February 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8

Weiqing Tang^*,, Yinyan Ma, Lin Jia, Yiannis A. Ioannou, Joanna P. Davies and Liqing Yu^1,

^* The 5th Clinical Hospital (Beijing Hospital), Peking University, and Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, Ministry of Health, Beijing, China
Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC
Department of Human Genetics, Mount Sinai School of Medicine, New York, NY

This work was supported by the American Heart Association Scientist Development Grant 0635261N (to L. Yu.) and the Department of Pathology, Wake Forest University School of Medicine.

Published, JLR Papers in Press, September 15, 2008.

¹ To whom correspondence should be addressed. e-mail: lyu{at}wfubmc.edu

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.

Supplementary key words Niemann-Pick C1-Like 1 • ATP-binding cassette • phytosterols • sterol absorption

Abbreviations: ABC, ATP-binding cassette; NPC1L1, Niemann-Pick C1-Like 1; RAP, receptor associated protein; TKO, triple knockout; WT, wild-type

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