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Journal of Lipid Research, Vol. 45, 1649-1659, September 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

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^1,*,

^* Departments of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110
Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO, 63110

¹ To whom correspondence should be addressed. e-mail: nod{at}wustl.edu

Recent studies have examined the role of the LDL receptor (LDLR) in regulating murine hepatic lipoprotein production and apolipoprotein B (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 apoB-100 secretion. Hepatic triglyceride production in vivo (using Triton WR-1339) was unchanged in wild-type (WT) C57BL/6, apobec-1^–/–, ldlr^–/–, and [apobec-1^–/–, ldlr^–/–] mice, while apoB-100 production (using [³⁵S]methionine incorporation) was increased >2-fold in [apobec-1^–/–, ldlr^–/–] mice. Although >90% of 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 WT, 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 apoB-100 with virtual elimination of posttranslational degradation.

These results directly support the suggestion that the LDLR regulates hepatic apoB-100 production and modulates secretion of small, triglyceride-rich particles, both in vivo and in vitro.

Supplementary key words VLDL secretion • apolipoprotein B-100 • lipoprotein biogenesis • atherosclerosis

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