PMID:13130124

Citation	Chen, Z, Fitzgerald, RL, Li, G, Davidson, NO and Schonfeld, G (2004) Hepatic secretion of apoB-100 is impaired in hypobetalipoproteinemic mice with an apoB-38.9-specifying allele. J. Lipid Res. 45:155-63
Abstract	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.
Links	PubMed Online version:10.1194/jlr.M300275-JLR200
Keywords	Alleles; Animals; Apolipoprotein B-100; Apolipoproteins B/biosynthesis; Apolipoproteins B/blood; Apolipoproteins B/genetics; Apolipoproteins B/metabolism; Apolipoproteins B/secretion; Cells, Cultured; Cholesterol/metabolism; Cytidine Deaminase/deficiency; Cytidine Deaminase/genetics; Cytidine Deaminase/metabolism; Fatty Liver/genetics; Fatty Liver/metabolism; Hepatocytes/cytology; Hepatocytes/metabolism; Hepatocytes/secretion; Hypobetalipoproteinemias/metabolism; Liver/drug effects; Liver/metabolism; Liver/secretion; Mice; Mice, Transgenic; Protease Inhibitors/pharmacology; Receptors, Lipoprotein/antagonists & inhibitors; Receptors, Lipoprotein/metabolism; Triglycerides/metabolism
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