title: Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport.
abstract: The fate of free cholesterol released after endocytosis of low-density lipoproteins remains obscure. Here we report that late endosomes have a pivotal role in intracellular cholesterol transport. We find that in the genetic disease Niemann-Pick type C (NPC), and in drug-treated cells that mimic NPC, cholesterol accumulates in late endosomes and sorting of the lysosomal enzyme receptor is impaired. Our results show that the characteristic network of lysobisphosphatidic acid-rich membranes contained within multivesicular late endosomes regulates cholesterol transport, presumably by acting as a collection and distribution device. The results also suggest that similar endosomal defects accompany the anti-phospholipid syndrome and NPC.
authors.affiliation: Department of Biochemistry, University of Geneva, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: M H
authors.initials: MH
authors.lastname: Beuchat
authors.forename: M
authors.initials: M
authors.lastname: Lindsay
authors.forename: S
authors.initials: S
authors.lastname: Frias
authors.forename: R D
authors.initials: RD
authors.lastname: Palmiter
authors.forename: H
authors.initials: H
authors.lastname: Sakuraba
authors.forename: R G
authors.initials: RG
authors.lastname: Parton
authors.forename: J
authors.initials: J
authors.lastname: Gruenberg
mesh_terms: D000818:Animals; D016736:Antiphospholipid Syndrome / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D004705:Endocytosis; D011992:Endosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism*; D050178:Monoglycerides; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D015032:Zinc / Q000494:pharmacology
chemical_list: D008246:Lysophospholipids; D008563:Membrane Lipids; D050178:Monoglycerides; D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; C012786:bis(monoacylglyceryl)phosphate; D002784:Cholesterol; D015032:Zinc