Do mammalian NPC1 and NPC2 play a role in intestinal cholesterol absorption?
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.
Dixit
Sayali S
SS
Center for Advanced Biotechnology and Medicine, 679 Hoes Lane, Piscataway, NJ 08854, USA.
Sleat
David E
DE
Stock
Ann M
AM
Lobel
Peter
P
D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D007408:Intestinal Absorption / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D000077296:Niemann-Pick C1 Protein; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012680:Sensitivity and Specificity; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
D001384:Azetidines; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; C497045:Npc2 protein, mouse; D011506:Proteins; D033921:Vesicular Transport Proteins; D002784:Cholesterol; D000069438:Ezetimibe