Knockout of the abetalipoproteinemia gene in mice: Reduced lipoprotein secretion in heterozygotes and embryonic lethality in homozygotes

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Abstract
Abetalipoproteinemia, an inherited human disease characterized by a near-complete absence of the apolipoprotein (apo) B-containing lipoproteins in the plasma, is caused by mutations in the gene for microsomal triglyceride transfer protein (MTP). We used gene targeting to knock out the mouse MTP gene ( Mttp ). In heterozygous knockout mice ( Mttp +/− ), the MTP mRNA, protein, and activity levels were reduced by 50%, in both liver and intestine. Compared with control mice ( Mttp +/+), chow-fed Mttp +/− mice had reduced plasma levels of low-density lipoprotein cholesterol and had a 28% reduction in plasma apoB100 levels. On a high-fat diet, the Mttp +/− mice exhibited a marked reduction in total plasma cholesterol levels, compared with those in Mttp +/+ mice. Both the livers of adult Mttp +/− mice and the visceral endoderm of the yolk sacs from Mttp +/− embryos manifested an accumulation of cytosolic fat. All homozygous embryos ( Mttp −/−) died during embryonic development. In the visceral endoderm of Mttp −/− yolk sacs, lipoprotein synthesis was virtually absent, and there was a marked accumulation of cytosolic fat droplets. In summary, half-normal MTP levels do not support normal levels of lipoprotein synthesis and secretion, and a complete deficiency of MTP causes lethal developmental abnormalities, perhaps because of an impaired capacity of the yolk sac to export lipids to the developing embryo.

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