Rab8-dependent recycling promotes endosomal cholesterol removal in normal and sphingolipidosis cells

Matts D Linder, Riikka-Liisa Uronen, Maarit Hölttä-Vuori, Peter van der Sluijs, Johan Peränen, Elina Ikonen, Matts Linder

Research output: Contribution to journalArticleScientificpeer-review

Abstract

The mechanisms by which low-density lipoprotein (LDL)-cholesterol exits the endocytic circuits are not well understood. The process is defective in Niemann-Pick type C (NPC) disease in which cholesterol and sphingolipids accumulate in late endosomal compartments. This is accompanied by defective cholesterol esterification in the endoplasmic reticulum and impaired ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux. We show here that overexpression of the recycling/exocytic Rab GTPase Rab8 rescued the late endosomal cholesterol deposition and sphingolipid mistrafficking in NPC fibroblasts. Rab8 redistributed cholesterol from late endosomes to the cell periphery and stimulated cholesterol efflux to the ABCA1-ligand apolipoprotein A-I (apoA-I) without increasing cholesterol esterification. Depletion of Rab8 from wild-type fibroblasts resulted in cholesterol deposition within late endosomal compartments. This cholesterol accumulation was accompanied by impaired clearance of LDL-cholesterol from endocytic circuits to apoA-I and could not be bypassed by liver X receptor activation. Our findings establish Rab8 as a key component of the regulatory machinery that leads to ABCA1-dependent removal of cholesterol from endocytic circuits.
Original languageEnglish
JournalMolecular Biology of the Cell
Volume18
Pages (from-to)47-56
Number of pages10
ISSN1059-1524
DOIs
Publication statusPublished - 2007
MoE publication typeA1 Journal article-refereed

Cite this

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title = "Rab8-dependent recycling promotes endosomal cholesterol removal in normal and sphingolipidosis cells",
abstract = "The mechanisms by which low-density lipoprotein (LDL)-cholesterol exits the endocytic circuits are not well understood. The process is defective in Niemann-Pick type C (NPC) disease in which cholesterol and sphingolipids accumulate in late endosomal compartments. This is accompanied by defective cholesterol esterification in the endoplasmic reticulum and impaired ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux. We show here that overexpression of the recycling/exocytic Rab GTPase Rab8 rescued the late endosomal cholesterol deposition and sphingolipid mistrafficking in NPC fibroblasts. Rab8 redistributed cholesterol from late endosomes to the cell periphery and stimulated cholesterol efflux to the ABCA1-ligand apolipoprotein A-I (apoA-I) without increasing cholesterol esterification. Depletion of Rab8 from wild-type fibroblasts resulted in cholesterol deposition within late endosomal compartments. This cholesterol accumulation was accompanied by impaired clearance of LDL-cholesterol from endocytic circuits to apoA-I and could not be bypassed by liver X receptor activation. Our findings establish Rab8 as a key component of the regulatory machinery that leads to ABCA1-dependent removal of cholesterol from endocytic circuits.",
author = "Linder, {Matts D} and Riikka-Liisa Uronen and Maarit H{\"o}ltt{\"a}-Vuori and Sluijs, {Peter van der} and Johan Per{\"a}nen and Elina Ikonen and Matts Linder",
year = "2007",
doi = "10.1091/mbc.E06-07-0575",
language = "English",
volume = "18",
pages = "47--56",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "AMERICAN SOCIETY FOR CELL BIOLOGY",

}

Rab8-dependent recycling promotes endosomal cholesterol removal in normal and sphingolipidosis cells. / Linder, Matts D; Uronen, Riikka-Liisa; Hölttä-Vuori, Maarit; Sluijs, Peter van der; Peränen, Johan; Ikonen, Elina; Linder, Matts.

In: Molecular Biology of the Cell, Vol. 18, 2007, p. 47-56.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Rab8-dependent recycling promotes endosomal cholesterol removal in normal and sphingolipidosis cells

AU - Linder, Matts D

AU - Uronen, Riikka-Liisa

AU - Hölttä-Vuori, Maarit

AU - Sluijs, Peter van der

AU - Peränen, Johan

AU - Ikonen, Elina

AU - Linder, Matts

PY - 2007

Y1 - 2007

N2 - The mechanisms by which low-density lipoprotein (LDL)-cholesterol exits the endocytic circuits are not well understood. The process is defective in Niemann-Pick type C (NPC) disease in which cholesterol and sphingolipids accumulate in late endosomal compartments. This is accompanied by defective cholesterol esterification in the endoplasmic reticulum and impaired ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux. We show here that overexpression of the recycling/exocytic Rab GTPase Rab8 rescued the late endosomal cholesterol deposition and sphingolipid mistrafficking in NPC fibroblasts. Rab8 redistributed cholesterol from late endosomes to the cell periphery and stimulated cholesterol efflux to the ABCA1-ligand apolipoprotein A-I (apoA-I) without increasing cholesterol esterification. Depletion of Rab8 from wild-type fibroblasts resulted in cholesterol deposition within late endosomal compartments. This cholesterol accumulation was accompanied by impaired clearance of LDL-cholesterol from endocytic circuits to apoA-I and could not be bypassed by liver X receptor activation. Our findings establish Rab8 as a key component of the regulatory machinery that leads to ABCA1-dependent removal of cholesterol from endocytic circuits.

AB - The mechanisms by which low-density lipoprotein (LDL)-cholesterol exits the endocytic circuits are not well understood. The process is defective in Niemann-Pick type C (NPC) disease in which cholesterol and sphingolipids accumulate in late endosomal compartments. This is accompanied by defective cholesterol esterification in the endoplasmic reticulum and impaired ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux. We show here that overexpression of the recycling/exocytic Rab GTPase Rab8 rescued the late endosomal cholesterol deposition and sphingolipid mistrafficking in NPC fibroblasts. Rab8 redistributed cholesterol from late endosomes to the cell periphery and stimulated cholesterol efflux to the ABCA1-ligand apolipoprotein A-I (apoA-I) without increasing cholesterol esterification. Depletion of Rab8 from wild-type fibroblasts resulted in cholesterol deposition within late endosomal compartments. This cholesterol accumulation was accompanied by impaired clearance of LDL-cholesterol from endocytic circuits to apoA-I and could not be bypassed by liver X receptor activation. Our findings establish Rab8 as a key component of the regulatory machinery that leads to ABCA1-dependent removal of cholesterol from endocytic circuits.

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JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

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