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Journal of Lipid Research, Vol. 45, 155-163, January 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Hepatic secretion of apoB-100 is impaired in hypobetalipoproteinemic mice with an apoB-38.9-specifying allele

Zhouji Chen^1,*, Robin L. Fitzgerald^*, Gang Li^2,*, Nicholas O. Davidson and Gustav Schonfeld^*

^* Divisions of Atherosclerosis, Nutrition, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110

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

Apolipoprotein B (apoB) truncation-specifying mutations cause familial hypobetalipoproteinemia (FHBL). Lipoprotein kinetics studies have shown that production rates of apoB-100 are reduced by 70–80% in heterozygous FHBL humans, instead of the expected 50%. To develop suitable mouse models to study the underlying mechanism, apoB-38.9-only (Apob^38.9/38.9) mice were crossbred with Apobec-1 knockout (Apobec-1^-/-) mice or apoB-100-only (Apob^100/100) mice to produce two lines of apoB-38.9 heterozygous mice that produce only apoB-38.9 and apoB-100, namely Apobec-1^-/-/Apob^38.9/+ and Apob^38.9/100 mice. In vivo rates of apoB-100 secretion were measured using [³⁵S]Met/Cys to label proteins and Triton WR-1339 to block apoB-100 VLDL lipolysis/uptake. Rates of secretion were reduced by 80%, rather than the expected 50%, in both Apobec-1^-/-/Apob^38.9/+ and Apob^38.9/100 mice compared with those of the respective Apobec-1^-/-/Apob^+/+ and Apob^100/100 control mice. Continuous labeling and pulse-chase experiments in primary hepatocyte cultures revealed that rates of apoB-100 synthesis by Apobec-1^-/-/Apob^38.9/+ and Apob^38.9/100 hepatocytes were reduced to the expected 50% of those of the respective controls, but the efficiency of secretion of apoB-100 was significantly lower in apoB-38.9 heterozygous hepatocytes.

The greater-than-expected decreases in apoB-100 production rates of FHBL heterozygous humans appear to be attributable to a defect in secretion rather than in the synthesis of apoB-100 from the unaffected apoB allele.

Supplementary key words VLDL secretion • gene targeting • animal model

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