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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1104.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Human LDL Receptor Enhances Sequestration of ApoE4 and VLDL Remnants on the Surface of Hepatocytes but Not Their Internalization in Mice

Michael Altenburg; Jose Arbones-Mainar; Lance Johnson; Jennifer Wilder; Nobuyo Maeda

From the Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill.

Correspondence to Dr Nobuyo Maeda, Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525. E-mail nobuyo{at}med.unc.edu

Objective— In humans, apolipoprotein (apo) E4 is associated with elevated plasma cholesterol levels and a high risk of developing atherosclerosis, whereas apoE2 is protective. Here we investigate the mechanism by which mice expressing human apoE isoforms recapitulate this association when they also express high levels of human low-density lipoprotein receptor (LDLR).

Methods and Results— Primary hepatocytes from apoE4 mice secreted less apoE into the medium than hepatocytes from apoE2 mice. Increased LDLR expression decreased this secretion and increased degradation of apoE4. An apoE4-GFP fusion protein expressed in the liver of apoE-deficient mice accumulated on the hepatocyte surface bordering the space of Disse in an LDLR-dependent manner. Fluorescence-labeled very low–density lipoprotein (VLDL) remnants accumulated on the hepatocyte surface in apoE4 mice with high LDLR, but they were internalized poorly. In contrast, apoE2-GFP did not accumulate on the hepatocyte surface even when the LDLR expression was high, but apoE2 mice with high LDLR internalized the remnants avidly without sequestering them on the hepatocyte surface.

Conclusions— The high affinity of apoE4 to the LDLR enhances VLDL sequestration on the hepatocyte surface but delays their internalization. This delay likely increases VLDL conversion to cholesterol-enriched remnants in apoE4 mice with high LDLR, and probably to LDL in humans with apoE4.

Increased LDLR expression enhances sequestration of apoE4 and VLDL on the hepatocyte surface but delays the internalization of VLDL. In contrast, apoE2, having low LDLR affinity, freely associates with VLDL in circulation and assists internalization when LDLR expression is high. This mechanism may contribute to the lipoprotein profiles associated with apoE isoforms.

Key Words: mouse models • lipoprotein metabolism • space of Disse • recombinant adenovirus

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