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J. Lipid Res.
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A more recent version of this article appeared on September 1, 2004

Papers In Press, published online ahead of print May 16, 2004
J. Lipid Res., doi:10.1194/jlr.M300505-JLR200
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Submitted on December 11, 2003
Revised on April 20, 2004
Accepted on May 14, 2004

Hepatic secretion of small lipoprotein particles in apobec-1-/- mice is regulated by the LDL receptor

Fatiha Nassir, Yan Xie, Bruce W. Patterson, Jianyang Luo, and Nicholas O. Davidson

Medicine, Washington University School of Medicine, St. Louis, MO 63110

Corresponding Author: nod{at}im.wustl.edu

Recent studies have examined the role of the low density lipoprotein receptor (LDLR) in regulating murine hepatic lipoprotein production and apolipoproteinB (apoB) secretion, with divergent conclusions from in-vivo versus in-vitro approaches. We have re-examined this question, both in-vivo and in-vitro using apobec-1-/- mice to model the pattern of human hepatic apoB100 secretion. Hepatic triglyceride production in-vivo (using Triton WR 1339) was unchanged in wild-type C57BL/6 (WT), apobec-1-/-, ldlr-/- and [apobec-1-/-, ldlr-/-] mice, while apoB100 production (using [35S]-methionine incorporation) was increased >2-fold in [apobec-1-/-, ldlr-/-] mice. Although >90% newly synthesized apoB floated within the d<1.006 fraction of serum from all genotypes, fast-performance liquid chromatography separation revealed that nascent triglyceride-rich particles from [apobec-1-/-, ldlr-/-] mice, but not wild-type, apobec-1-/-, or ldlr-/- mice, distributed into smaller (intermediate and LDL-sized) particles. Studies in isolated hepatocytes from these different genotypes confirmed secretion of smaller particles exclusively from [apobec-1-/-, ldlr-/-] mice, and pulse-chase analysis demonstrated increased secretion of apoB100 with virtual elimination of post-translational degradation. These results directly support the suggestion that the LDLR regulates hepatic apoB100 production and modulates secretion of small, triglyceride-rich particles, both in-vivo and in-vitro.


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