Key result
In mice with an apoB-38.9-specifying allele, in vivo rates of apoB-100 secretion were reduced by 80% compared to controls, indicating a defect in secretion rather than synthesis.
The greater-than-expected decrease in apoB-100 production in familial hypobetalipoproteinemia heterozygotes is driven by a defect in secretion rather than synthesis from the unaffected allele.
Mouse models of apoB-38.9 may clarify FHBL mechanisms; hypothesis-generating, with no clinical implications yet.
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.
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Chen et al. (2004) studied Familial hypobetalipoproteinemia. apoB-38.9-specifying allele vs. Wild-type/control mice (Apobec-1(-/-)/Apob(+/+) and Apob(100/100)) was evaluated on In vivo rates of apoB-100 secretion. In mice with an apoB-38.9-specifying allele, in vivo rates of apoB-100 secretion were reduced by 80% compared to controls, indicating a defect in secretion rather than synthesis.
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