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Papers In Press, published online ahead of print September 16, 2003
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Medicine Dept., Washington University School of Medicine, St. Louis, MO 63110
Corresponding Author: zchen{at}im.wustl.edu
ApoB Truncation-specifying mutations cause familial hypobetalipoproteinemia (FHBL). Lipoprotein kinetic 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 (apob38.9/38.9) mice were crossbred with apobec-1 knockout (apobec-1-/-) mice or apoB-100-only (apob100/100) mice to produce 2 lines of apoB-38.9 heterozygous mice that produce only apoB-38.9 and apoB-100, namely apobec-1-/-/apob38.9/+ and apob38.9/100 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-/-/apob38.9/+ and apob38.9/100 mice, compared to those of their respective apobec-1-/-/apob+/+ and apob100/100 control mice. Continuous labeling and pulse-chase experiments in primary hepatocyte cultures revealed that rates of apoB-100 synthesis by apobec-1-/-/apob38.9/+ and apob38.9/100 hepatocytes were reduced to the expected 50% of those of their respective controls but efficiency of secretion of apoB-100 was significantly lower in apoB-38.9 heterozygous hepatocytes. The larger-than-expected decreases in apoB-100 production rates of FHBL heterozygous humans appear to be due to a defect in secretion rather than in the synthesis of apoB-100 from the unaffected apoB allele.
Revised on August 28, 2003
Accepted on September 12, 2003
Hepatic secretion of apolipoprotein B-100 is impaired in hypobetalipoproteinemic mice with an apolipoprotein B-38.9-specifying allele
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