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J Biol Chem, Vol. 275, Issue 12, 8564-8571, March 24, 2000

Apolipoprotein E Is Resistant to Intracellular Degradation in Vitro and in Vivo
EVIDENCE FOR RETROENDOCYTOSIS^*

Patrick C. N. Rensen^§, Miek C. Jong^¶, Leonie C. van Vark^¶, Hans van der Boom^¶, Wendy L. Hendriks^¶, Theo J. C. van Berkel, Erik A. L. Biessen, and Louis M. Havekes^¶

From the  Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, University of Leiden, Sylvius Laboratory, P. O. Box 9503, 2300 RA Leiden, ^¶ TNO-Prevention and Health, Gaubius Laboratory, P O. Box 2215, 2301 CE Leiden, and the  Departments of Cardiology and General Internal Medicine, Leiden University Medical Center, P. O. Box 9600, 2300 RC Leiden, The Netherlands

Apolipoprotein E (apoE) is an important determinant for the uptake of triglyceride-rich lipoproteins and emulsions by the liver, but the intracellular pathway of apoE following particle internalization is poorly defined. In the present study, we investigated whether retroendocytosis is a unique feature of apoE as compared with apoB by studying the intracellular fate of very low density lipoprotein-sized apoE-containing triglyceride-rich emulsion particles and LDL after LDLr-mediated uptake. Incubation of HepG2 cells with [³H]cholesteryl oleate-labeled particles at 37 °C led to a rapid release of [³H]cholesterol within 30 min for both LDL and emulsion particles. In contrast, emulsion-derived ¹²⁵I-apoE was more resistant to degradation (120 min) than LDL-derived ¹²⁵I-apoB (30 min). Incubation at 18 °C, which allows endosomal uptake but prevents lysosomal degradation, with subsequent incubation at 37 °C resulted in a time-dependent release of intact apoE from the cells (up to 14% of the endocytosed apoE at 4 h). The release of apoE was accelerated by the presence of protein-free emulsion (20%) or high density lipoprotein (26%). Retroendocytosis of intact particles could be excluded since little intact [³H]cholesteryl oleate was released (<3%). In contrast, the degradation of LDL was complete with virtually no secretion of intact apoB into the medium. The intracellular stability of apoE was also demonstrated after hepatic uptake in C57Bl/6 mice. Intravenous injection of ¹²⁵I-apoE and [³H]cholesteryl oleate-labeled emulsions resulted in efficient LDLr-mediated uptake of both components by the liver (45-50% of the injected dose after 20 min). At 1 h after injection, only 15-20% of the hepatic ¹²⁵I-apoE was degraded, whereas 75% of the [³H]cholesteryl oleate was hydrolyzed. From these data we conclude that following LDLr-mediated internalization by liver cells, apoE can escape degradation and can be resecreted. This sequence of events may allow apoE to participate in its hypothesized intracellular functions such as mediator of the post-lysosomal trafficking of lipids and very low density lipoprotein assembly.

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