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J. Biol. Chem., Vol. 277, Issue 16, 14135-14145, April 19, 2002

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Hypobetalipoproteinemic Mice with a Targeted Apolipoprotein (Apo) B-27.6-specifying Mutation
IN VIVO EVIDENCE FOR AN IMPORTANT ROLE OF AMINO ACIDS 1254-1744 OF ApoB IN LIPID TRANSPORT AND METABOLISM OF THE ApoB-CONTAINING LIPOPROTEIN^*

Zhouji Chen, Robin L Fitzgerald, and Gustav Schonfeld

From the Division of Atherosclerosis, Nutrition and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Carboxyl-terminal deletion of apoB-100 may impair its triglyceride (TG)-transporting capability and alter its catabolism. Here, we compare our newly generated apoB gene (Apob)-targeted apoB-27.6-bearing mice to our previously reported apoB-38.9 mice to understand further the relationship between the size of a truncated apoB variant and its function/metabolism in vivo. The apoB-27.6-specifying mutation produces a premature stop codon six amino acids (aa) downstream of the last codon of mouse Apob exon 24 (corresponding to aa 1254 of human apoB-100). ApoB-27.6 transcripts were 3- and 5-fold more abundant than apoB wild type and apoB-38.9 transcripts in the liver. Likewise, hepatic secretion rates of apoB-27.6 were 7-fold higher than those of apoB-48 and apoB-38.9. In contrast, apoB-27.6 heterozygotes (Apob^27.6/+) had lower hepatic TG secretion rates and higher liver TG contents than both apoB-38.9 heterozygotes (Apob^38.9/+) and apoB wild type mice (Apob^+/+). ApoB-27.6 was secreted by Apob^27.6/+ hepatocytes as dense high density lipoprotein particles. Moreover, despite its high secretion rates, apoB-27.6 was barely detectable in plasma. Disruption of apoE gene in Apob^38.9/+ and Apob^27.6/+ dramatically increased plasma levels of apoB-38.9 as well as apoB-48 but caused no change in plasma apoB-27.6 concentrations. Finally, the birth rate of apoB-27.6 homozygotes (Apob^27.6/27.6) from intercrosses of Apob^27.6/+ was 7-fold lower than that of Apob^38.9/38.9 from Apob^38.9/+ intercrosses (1.8% versus 12%). Crossbreeding of Apob^27.6/27.6 and Apob^38.9/38.9 produced viable Apob^27.6/38.9 offspring, but Apob^27.6/27.6 intercrosses produced no offspring. Together, these results demonstrate in vivo that the apoB-27.6-apoB-38.9 peptide segment (aa 1254-1744) plays a critical role, not only in supporting hepatic TG-secretion and in modulating catabolism of apoB-containing lipoproteins, but also in normal mouse embryonic development.

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