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Vol. 18, Issue 1, 47-56, January 2007
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*Institute of Biomedicine/Anatomy and Institute of Biotechnology, University of Helsinki, FI-00014 Helsinki, Finland; and Department of Cell Biology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Submitted July 3, 2006;
Revised September 13, 2006;
Accepted October 10, 2006
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.
Address correspondence to: Elina Ikonen (elina.ikonen{at}helsinki.fi)
Abbreviations used: ABCA1, ATP-binding cassette transporter A1; apoA-I, apolipoprotein A-I; CTxB, cholera toxin subunit B; ER, endoplasmic reticulum; GDI, GDP dissociation inhibitor; GFP, green fluorescent protein; Lamp1, lysosome-associated membrane protein 1; LDL, low-density lipoprotein; LXR, liver X receptor; NPC, Niemann–Pick disease type C; RNAi, RNA interference; SFV, Semliki Forest virus; shRNA, short hairpin RNA.
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