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J. Biol. Chem., Vol. 278, Issue 13, 11670-11675, March 28, 2003
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From the The importance of hepatocyte-derived
apolipoprotein (apo) E in the clearance of remnant lipoproteins in the
liver is controversial. To address this controversy, we compared
remnant clearance in two mouse models in which apoE is primarily
derived either from hepatocytes or from an extrahepatic source.
Hypomorphic apoE mice universally express reduced levels of apoE in all
tissues, with the liver remaining the primary source of apoE. This
mouse model of hepatocyte-derived apoE was compared with
Apoe
Hepatocyte-derived ApoE Is More Effective than
Non-hepatocyte-derived ApoE in Remnant Lipoprotein Clearance*
§,§,,,§
**
Gladstone Institutes of Cardiovascular
Disease and Neurological Disease, San Francisco, California
94141-9100, the § Cardiovascular Research Institute and
Department of Pathology, University of California, San
Francisco, California 94143, and the ¶ Department of Medicine,
Vanderbilt University, Nashville, Tennessee 37232
/ mice transplanted with mouse bone
marrow as a model of primarily non-hepatocyte-derived apoE.
Immunohistochemical analysis of liver sections revealed that only the
hepatocyte-derived apoE model had detectable levels of apoE on hepatic
sinusoidal surfaces. The non-hepatocyte-derived apoE model with plasma
apoE levels similar to those in the hepatocyte-derived model had 2-fold
more total plasma cholesterol, 4-fold more total plasma triglycerides, and 8-fold higher levels of apoB48, similar to
Apoe/ mice. Both the hepatocyte-derived and
the non-hepatocyte-derived apoE models had delayed clearance of an
infused bolus of 125I-labeled remnants compared with
wild-type mice. However, after 3 h, plasma remnants reached
wild-type levels only in the hepatocyte-derived apoE model, which had
accumulated 70 ± 5% of wild-type levels of remnants in the liver
while the non-hepatocyte-derived apoE model had accumulated only
38 ± 4%. These results demonstrate the existence of a role for
both hepatically derived and localized apoE in remnant
clearance. This role likely represents the enrichment of
remnants sequestered on hepatocyte, with hepatocyte-derived apoE,
facilitating their receptor-mediated internalization.
*
This work was supported in part by NIH Grant HL47660 (to
K. H. W.), by Grant 10KT-0318 from the University of California
Tobacco-Related Disease Research Program and a fellowship from the
Heart and Stroke Foundation of Canada (to R. L. R.), and by NIH
Grants 57986 (to S. F.) and 53989 to (M. F. L.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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