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J. Biol. Chem., Vol. 283, Issue 38, 25920-25927, September 19, 2008

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Endocytosis of Apolipoprotein A-V by Members of the Low Density Lipoprotein Receptor and the Vps10p Domain Receptor Families^*

Stefan K. Nilsson, Stine Christensen, Merete K. Raarup, Robert O. Ryan^¶, Morten S. Nielsen, and Gunilla Olivecrona¹

From the Department of Medical Biosciences/Physiological Chemistry, Umeå University, SE90187 Umeå, Sweden, the MIND-Center, Department of Medical Biochemistry, and the Stereology and Electron Microscopy Research Laboratory, University of Aarhus, 8000 Aarhus, Denmark, and the ^¶Center for Prevention of Obesity, Diabetes, and Cardiovascular Diseases, Children's Hospital Oakland Research Institute, Oakland, California 94609

Apolipoprotein A-V (apoA-V) is present in low amounts in plasma and has been found to modulate triacylglycerol levels in humans and in animal models. ApoA-V displays affinity for members of the low density lipoprotein receptor (LDL-R) gene family, known as the classical lipoprotein receptors, including LRP1 and SorLA/LR11. In addition to LDL-A binding repeats, the mosaic receptor SorLA/LR11 also possesses a Vps10p domain. Here we show that apoA-V also binds to sortilin, a receptor from the Vsp10p domain gene family that lacks LDL-A repeats. Binding of apoA-V to sortilin was competed by neurotensin, a ligand that binds specifically to the Vps10p domain. To investigate the biological fate of receptor-bound apoA-V, binding experiments were conducted with cultured human embryonic kidney cells transfected with either SorLA/LR11 or sortilin. Compared with nontransfected cells, apoA-V binding to SorLA/LR11- and sortilin-expressing cells was markedly enhanced. Internalization experiments, live imaging studies, and fluorescence resonance energy transfer analyses demonstrated that labeled apoA-V was rapidly internalized, co-localized with receptors in early endosomes, and followed the receptors through endosomes to the trans-Golgi network. The observed decrease of fluorescence signal intensity as a function of time during live imaging experiments suggested ligand uncoupling in endosomes with subsequent delivery to lysosomes for degradation. This interpretation was supported by experiments with ¹²⁵I-labeled apoA-V, demonstrating clear differences in degradation between transfected and nontransfected cells. We conclude that apoA-V binds to receptors possessing LDL-A repeats and Vsp10p domains and that apoA-V is internalized into cells via these receptors. This could be a mechanism by which apoA-V modulates lipoprotein metabolism in vivo.

Received for publication, April 8, 2008 , and in revised form, June 24, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant HL-073061. This work was also supported by Swedish Research Council Grant 12203 and King Gustav V and Queen Victoria Research Foundation. The MIND-Center is sponsored by The Lundbeck Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2 and Movies 1 and 2.

¹ To whom correspondence should be addressed: Bldg. 6M, 3rd Floor, Umeå University Hospital Area, SE-901 87 Umeå, Sweden.

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