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Transport of lipids from Golgi to plasma membrane is defective in Tangier disease patients and Abc1-deficient mice


Mutations in the gene encoding ATP-binding cassette transporter 1 ( ABC1) have been reported in Tangier disease1,2,3 (TD), an autosomal recessive disorder that is characterized by almost complete absence of plasma high-density lipoprotein (HDL), deposition of cholesteryl esters in the reticulo-endothelial system4 (RES) and aberrant cellular lipid trafficking5,6,7,8,9,10,11,12. We demonstrate here that mice with a targeted inactivation of Abc1 display morphologic abnormalities and perturbations in their lipoprotein metabolism concordant with TD. ABC1 is expressed on the plasma membrane and the Golgi complex, mediates apo-AI associated export of cholesterol and phospholipids from the cell, and is regulated by cholesterol flux. Structural and functional abnormalities in caveolar processing and the trans-Golgi secretory pathway of cells lacking functional ABC1 indicate that lipid export processes involving vesicular budding between the Golgi and the plasma membrane are severely disturbed.

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Figure 1: Effect of Abc1 genotype on lipoprotein subclasses.
Figure 2: Representative transmission electron micrographs demonstrating the ultrastructural characteristics of small intestinal sections in wild-type and Abc1−/− mice.
Figure 4: The fluorescent analogue of ceramide, N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminohexanoyl-D- erythro-sphingosine (C6-NBD-Cer), used to study cellular lipid transport.
Figure 3: Cholesterol and phospholipid efflux mediated by apo-AI in wild-type and Abc1−/− mouse fibroblasts

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We thank D. Szabó for polarization microscopy; R. Knuechel-Clarke for histological evaluation of mouse tissues; and A. Forster-Kreuzer for expert technical assistance. The fat-supplemented mouse diet was provided by S. Zaiss (Bayer AG). This work was supported by the Deutsche Forschungsgemeinschaft (grant Dr348/2-1) and Bayer AG (G.S.), institutional grants from the CNRS and INSERM, specific grants from ARC, LLNC and CNRS, and support by Pfizer, Inc. (G.C.). E.O. received support from the Alexander von Humboldt Foundation. C.B. was supported by an ARC fellowship.

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Correspondence to Gerd Schmitz.

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Orsó, E., Broccardo, C., Kaminski, W. et al. Transport of lipids from Golgi to plasma membrane is defective in Tangier disease patients and Abc1-deficient mice. Nat Genet 24, 192–196 (2000).

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