Biochem. J. (2007) 408
(1–5) (Printed in Great Britain)
Accelerated Publication
Do mammalian NPC1 and NPC2 play a role in intestinal cholesterol absorption?
Sayali S. DIXIT*†‡, David E. SLEAT*§, Ann M. STOCK*‡¶1 and Peter LOBEL*§1
*Center for Advanced Biotechnology and Medicine, 679 Hoes Lane, Piscataway, NJ 08854, U.S.A., †675 Hoes Lane, Piscataway, NJ 08854, U.S.A., ‡Department of Biochemistry, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School (UMDNJ–RWJMS), Piscataway, NJ 08854, U.S.A., §Department of Pharmacology, UMDNJ–RWJMS, Piscataway, NJ 08854, U.S.A., and ¶Howard Hughes Medical Institute, Piscataway, NJ 08854, U.S.A.
NPC1L1 (Niemann–Pick C1-like 1), the pharmacological target of the cholesterol-uptake inhibitor ezetimibe, is a transporter localized on the brush border of enterocytes. Although this protein plays a key role in intestinal uptake of sterols, multiple molecular events that underlie intestinal cholesterol absorption have not been fully characterized. Two proteins that might be involved in this process are NPC1 and NPC2 (Niemann–Pick disease type C proteins 1 and 2), which function in the endosomal/lysosomal cholesterol egress pathway and whose deficiency results in NPC (Niemann–Pick type C) disease. The involvement of these proteins in intestinal cholesterol absorption was examined in mutant mice lacking either NPC1 or NPC2. Our data indicate that deficiencies in either protein do not have an effect on cholesterol uptake or absorption. This contrasts with recent results obtained for the fruitfly Drosophila melanogaster, which indicate that a deficiency of NPC1 (dNPC1a being its Drosophila homologue) leads to activation of an NPC1L1 (Drosophila homologue dNPC1b)-independent cholesterol uptake pathway, underscoring fundamental differences in mammalian and non-mammalian cholesterol metabolism.
Key words: cholesterol transport, ezetimibe, lysosomal protein, Niemann–Pick type C disease (NPC disease), Niemann–Pick C1-like 1 (NPC1L1).
Abbreviations used: dNPC1a and dNPC1b, putative Drosophila orthologues of mammalian NPC1 (Niemann–Pick disease type C protein 1) and NPC1L1 (Niemann–Pick C1-like 1) respectively; LDL, low-density lipoprotein; NPC, Niemann–Pick type C; NPC1L1, Niemann–Pick C1-like; NPC1 and NPC2, Niemann–Pick disease type C proteins 1 and 2; SSD, sterol-sensing domain.
1To whom correspondence should be addressed (email lobel@cabm.rutgers.edu or stock@cabm.rutgers.edu).
Received 27 August 2007/17 September 2007; accepted 19 September 2007
Published as BJ Immediate Publication 19 September 2007, doi:10.1042/BJ20071167
© The Authors Journal compilation © 2007 Biochemical Society
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