title: Multiple plasma membrane receptors but not NPC1L1 mediate high-affinity, ezetimibe-sensitive cholesterol uptake into the intestinal brush border membrane.
abstract: We compared cholesterol uptake into brush border membrane vesicles (BBMV) made from the small intestines of either wild-type or Niemann-Pick C1-like 1 (NPC1L1) knockout mice to elucidate the contribution of NPC1L1 to facilitated uptake; this uptake involves cholesterol transport from lipid donor particles into the BBM of enterocytes. The lack of NPC1L1 in the BBM of the knockout mice had no effect on the rate of cholesterol uptake. It follows that NPC1L1 cannot be the putative high-affinity, ezetimibe-sensitive cholesterol transporter in the brush border membrane (BBM) as has been proposed by others. The following findings substantiate this conclusion: (I) NPC1L1 is not a brush border membrane protein but very likely localized to intracellular membranes; (II) the cholesterol absorption inhibitor ezetimibe and its analogues reduce cholesterol uptake to the same extent in wild-type and NPC1L1 knockout mouse BBMV. These findings indicate that the prevailing belief that NPC1L1 facilitates intestinal cholesterol uptake into the BBM and its interaction with ezetimibe is responsible for the inhibition of this process can no longer be sustained.
authors: Laboratorium für Organische Chemie, ETH Zürich, CH-8093 Zürich, Switzerland.
authors: Martin
authors: M
authors: Knöpfel
authors: Joanna P
authors: JP
authors: Davies
authors: Phu T
authors: PT
authors: Duong
authors: Lisbet
authors: L
authors: Kvaernø
authors: Erick M
authors: EM
authors: Carreira
authors: Michael C
authors: MC
authors: Phillips
authors: Yiannis A
authors: YA
authors: Ioannou
authors: Helmut
authors: H
authors: Hauser
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology*; D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000033:anatomy & histology / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D002784:Cholesterol; D000069438:Ezetimibe