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Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption
Scott W. Altmann,1*Harry R. Davis, Jr.,1Li-ji Zhu,1Xiaorui Yao,1Lizbeth M. Hoos,1Glen Tetzloff,1Sai Prasad N. Iyer,1Maureen Maguire,2Andrei Golovko,2Ming Zeng,2Luquan Wang,2Nicholas Murgolo,2Michael P. Graziano1
Dietary cholesterol consumption and intestinal cholesterol absorptioncontribute to plasma cholesterol levels, a risk factor for coronaryheart disease. The molecular mechanism of sterol uptake fromthe lumen of the small intestine is poorly defined. We showthat Niemann-Pick C1Like 1(NPC1L1) protein plays a criticalrole in the absorption of intestinal cholesterol. NPC1L1 expressionis enriched in the small intestine and is in the brush bordermembrane of enterocytes. Although otherwise phenotypically normal,NPC1L1-deficient mice exhibit a substantial reduction in absorbedcholesterol, which is unaffected by dietary supplementationof bile acids. Ezetimibe, a drug that inhibits cholesterol absorption,had no effect in NPC1L1 knockout mice, suggesting that NPC1L1resides in an ezetimibe-sensitive pathway responsible for intestinalcholesterol absorption.
1 Department of Cardiovascular/Endocrine Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ, 07033–0539, USA. 2 Department of Discovery Technologies, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ, 07033–0539, USA.
Present address: GenScript Corporation, 100 Menlo Park Drive,Suite 316, Edison, NJ, 08837, USA.
* To whom correspondence should be addressed. E-mail: scott.altmann{at}spcorp.com
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Eric L. Klett and Shailesh B. Patel (20 February 2004) Science303 (5661), 1149.
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46, 2468-2476
|Abstract »|Full Text »|PDF »
Intestinal cholesterol absorption is substantially reduced in mice deficient in both ABCA1 and ACAT2.
R. E. Temel, R. G. Lee, K. L. Kelley, M. A. Davis, R. Shah, J. K. Sawyer, M. D. Wilson, and L. L. Rudel (2005)
J. Lipid Res.
46, 2423-2431
|Abstract »|Full Text »|PDF »
The Forgotten Majority: Unfinished Business in Cardiovascular Risk Reduction.
Carotenoid Transport Is Decreased and Expression of the Lipid Transporters SR-BI, NPC1L1, and ABCA1 Is Downregulated in Caco-2 Cells Treated with Ezetimibe.
A. During, H. D. Dawson, and E. H. Harrison (2005)
J. Nutr.
135, 2305-2312
|Abstract »|Full Text »|PDF »
Supratherapeutic Response to Ezetimibe Administered with Cyclosporine.
S. L Koshman, L. D Lalonde, I. Burton, W. J Tymchak, and G. J Pearson (2005)
Ann. Pharmacother.
39, 1561-1565
|Abstract »|Full Text »|PDF »
Caveolin-1 Is Not Required for Murine Intestinal Cholesterol Transport.
M. A. Valasek, J. Weng, P. W. Shaul, R. G. W. Anderson, and J. J. Repa (2005)
J. Biol. Chem.
280, 28103-28109
|Abstract »|Full Text »|PDF »
A simple and rapid method to measure cholesterol binding to P450s and other proteins.
The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).
M. Garcia-Calvo, J. Lisnock, H. G. Bull, B. E. Hawes, D. A. Burnett, M. P. Braun, J. H. Crona, H. R. Davis Jr., D. C. Dean, P. A. Detmers, et al. (2005)
PNAS
102, 8132-8137
|Abstract »|Full Text »|PDF »
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